Apoptosis signal-regulating kinase 1 inhibitors

ABSTRACT

The present invention relates to apoptosis signal-regulating kinase 1 (“ASK1”) inhibiting compounds of the formula 
     
       
         
         
             
             
         
       
     
     wherein the variables are as defined herein. The invention also relates to pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/075,121 filed Jun. 24, 2008, which is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to compounds that may be used to inhibitapoptosis signal-regulating kinase 1 (ASK1) as well as compositions ofmatter, kits and articles of manufacture comprising these compounds. Theinvention also relates to methods for inhibiting ASK1 and treatmentmethods using compounds according to the present invention. In addition,the invention relates to methods of making the compounds of the presentinvention, as well as intermediates useful in such methods. Inparticular, the present invention relates to ASK1 inhibitors,compositions of matter, kits and articles of manufacture comprisingthese compounds, methods for inhibiting ASK1, and methods andintermediates useful for making the inhibitors.

BACKGROUND OF THE INVENTION

Apoptosis signal-regulating kinase 1 (ASK1), is a member of themitogen-activated protein kinases (MAPKs) family, which are members ofthe serine/threonine kinase family. Wang et al. J. Biol. Chem. 1996,271, 31607-31611, Ichijo et al. Science 1997, 275, 90-94. ASK1 is alsoknown as mitogen-activated protein kinase kinase kinase 5 (MAPKKK5,MAP3K5), MAP/ERK kinase kinase 5 (MEKK5), MEK kinase 5, MEKK5, MAP/ERKkinase kinase 5. The protein kinase composes of 1375 amino acidsencompassing 11 kinase subdomains; particularly a serine/threoninekinase domain in the middle part of the molecule with long NH— amdCOOH-terminal flanking regions. Wang et al. J. Biol. Chem. 1996, 271,31607-31611, Ichijo et al. Science 1997, 275, 90-94; Tobiume et al.Biochem. Biophys. Res. Commun. 1997, 239, 905-910; U.S. Pat. Nos.6,080,546 and 6,194,187. The nucleotide sequence of ASK1 is accessiblein the protein databases by the accession number NM_(—)005923. ASK1 isubiquitously expressed with the highest expression in the heart,pancreas, testis, and ovaries.

The MAP kinases mediate signal transduction from the cell surface to thenucleus via phosphorylation cascades. Egan and Weinbery Nature 1993,365, 781-783.

The MAPK cascades are multifunctional intracellular signaling pathwaysthat are evolutionarily conserved in all eukaryotic cells. Widmann etal. Physiol Rev 1999, 79, 143-180; Kyriakis and Avruch, J. Physiol Rev2001, 81, 807-869; Ichijo Oncogene 1999, 18:6087-6093. All eukaryoticcells possess multiple MAPK pathways. In mammalian cells, three MAPKcascades that converge on ERKs, c-Jun N-terminal kinases (JNKs), and p38MAP kinases have been extensively characterized. Egan and WeinberyNature 1993, 365, 781-783; Boulton et al. Cell 1994, 65, 663-675; andZhou et al. J. Biol. Chem. 1995, 270, 12665-12669 (the MAPK/ERKpathway); Derujard et al. Cell 1994, 76, 1025-1037; Galcheva-Gargova etal. Science 1994, 265, 806-808; Minden et al. Mol. Cell. Biol. 1994, 14,6683-6688 (the c-Jun N-terminal kinase (JNK) pathway; and Lee et al.Science 1994, 265, 808-811, (the p38 MAPK pathways). ERK pathway isactivated by various growth factors and closely linked to the regulationof cell cycle. The JNK and p38 pathways are preferentially activated byvarious cytotoxic stress such as UV radiation, X-ray, heat shock,osmotic shock, oxidative stress and pro-inflammatory cytokines such astumor necrosis factor (TNF) and interleukin-1. Tibbles and Woodgett,Cell Mol, Life Sci. 1999, 55:1230-1254. JNK and p38 are thus also calledstress-activated protein kinases (SAPKs).

Each MAPK cascade involves three classes of serine/threonine kinases,MAPK, MAPK kinanse (MAP2K) and MAP2K kinase (MAP3K). In the MAPKsignaling cascades, MAP3K phosphorylates and thereby activates MAP2K inturn phosphorylates and activates MAPK. Activated MAPK may translocateto the cell nucleus and regulate the activities of transcription factorsand thereby control gene expression. Sturgill and Wu, Biochim. Biophys.Acta 1993, 1092, 350; Nishida and Gotoh, Trends Biochem. Sci. 1993, 18,128; Errede and Levin Curr. Opin. Cell Biol. 1993, 5, 254; MarshallCurr. Opin. Genet. Dev. 1994, 82.

MAP3Ks play pivotal roles in sensing and signaling of cellular andenvironmental stress. The MAP3Ks in the JNK and p38 pathways are highlydivergent in number and structure. At least eleven MAP3Ks have beenidentified upstream of JNK, each of which activates single or multipledownstream MAPK cascades. This diversity and complexity are consistentwith the variety of stimuli that activate MAPK pathways. Kyriakis andAvruch Physiol. Rev. 2001, 81, 807-869.

One of the important biological responses mediated through thesestress-activated MAP kinase pathways appears to be the decision of cellfate by regulating apoptosis. The possible roles of the JNK pathway inpro-apoptosis signaling have been demonstrated by knockout mousestudies. Yang et al. Nature 1997, 389:865-870; Sabapathy et al. Curr.Biol. 1999, 9:116-125; Kuan et al. Neuron 1999, 22:667-676. Severallines of evidence have also suggested the pro-apoptotic roles of the p38pathway. Xia et al. Science 1995, 270:1326-1331; Kawaski et al. J. Biol.Chem. 1997, 272:18518-18521; Harper and LoGrasso et al. Cell Signal.2001, 13:299-310.

ASK1 was originally identified as an apoptosis-inducing MAP3K. ASK1regulates the p38 and JNK pathways by directly phosphorylating andthereby activating their respective MAPKKs, MKK4(SEK1)/MKK7 andMKK3/MKK6. Wang et al. J. Biol. Chem. 1996, 271, 31607-31611; Ichijo etal. Science 1997, 275, 90-94. The activity of ASK1 is tightly regulated;a ubiquitously expressed reduction/oxidation protein thioredoxin (Trx)binds to the N-terminal and inhibits its activity. ASK1 is activated byvarious cytotoxic stresses including oxidative stress, endoplasmicreticulum (ER) stress, and calcium overload, and by receptor-mediatedinflammatory signals such as tumor necrosis factor (TNF) and endotoxiclipopolysaccharide (LPS). Hayakaw et al. Microbes and Infection 2006, 8,1098-1107; Saitoh et al EMBO J. 1998, 17:2596-2606; Nishitoh et al.Genes Dev. 2002, 16:1345-1355; Takeda et al. EMBO Rep. 2004, 5, 161-166;Nishitoh et al. Mol Cell 1998, 2,389-395; Matsukawa et al. Nat Immunol2005, 6, 587-592. It has been shown that ASK1 is required for apoptosisinduced by oxidative stress, TNF and ER stresses. Nishitoh et al. GenesDev. 2002, 16:1345-1355; Matsukawa et al. Nat Immunol 2005, 6, 587-592;Tobiume et al. EMBO Rep. 2001, 2:222-228. Overexpression of wild-type orconstitutively active ASK1 induces apoptosis in various cells throughmitochondria-dependent caspase activation. Saitoh et al EMBO J. 1998, 17:2596-2606; Kanamoto et al. Mol. Cell Biol. 2000, 20, 196-204; Hatai etal. J. Biol. Chem. 2000, 275, 26576-26588.

Recent studies revealed that ASK1 contributes not only to regulation ofcell death but also has diverse functions in the decision of cell fatesuch as cytokine responses, cell differentiation, and innate immuneresponses. Matsukawa et al. J Biochem. (Toyko) 2004, 136, 261-265.Sayama et al. J. Biol. Chem. 2000, 276:999-1004; Takeda et al. J. Biol.Chem. 2000, 275:9805-9813; Sagasti et al. Cell 2001, 105:221-232; Kim etal. Science 2002, 297:623-626; Nishitoh et al. Genes Dev. 2002,16:1345-1355; Matsukawa et al. Nat Immunol 2005, 6, 587-592; Tobiume etal. EMBO Rep. 2001, 2:222-228; Imoto, et al. Diabetes 2006,55:1197-1204. Constitutively active ASK1 induces neurite outgrowth inPC12 cells. ASK1 is activated by CaMKII, which activates ASK1-p38pathway in neurons, suggesting that ASK1 might play critical roles insynaptic plasticity. Moreover, TRAF6-ASK1-p38 pathway plays an essentialrole in inflammatory and innate immune responses. Hayakawa et al.Microbes and Infection 2006, 8, 1098-1107. It has also been demonstratedthat ASK1 has a role in the pathogenesis of TNF-α-induced insulinresistance. Overexpression of wild-type ASK1 increases serinephosphorylation of insulin receptor substrate (IRS)-1, and decreasesinsulin-stimulated tyrosine phosphorylation of IIRS-1, leading to impairinsulin signaling. Imoto, et al. Diabetes 2006, 55:1197-1204.

ASK1 is thus a pivotal component not only in stress-induced cell deathbut also in a broad range of biological activities in order for cells toadapt to or oppose various stresses. Modulating the activity of ASK1potentially have beneficial effect in treating or preventing a widerange of diseases and conditions including, but not limited to,cardiovascular diseases, inflammatory diseases, autoimmune diseases,destructive bone disorders, neurodegenerative disorders, and metabolicdiseases such as diabetes. Thompson, Science 1995, 267, 1456-1462; Yuanand Yanker Nature 2000, 407, 802-809; Los et al. Immunity 1999, 10,629-639.

Currently, there are no known therapeutical agents that effectivelyinhibit the expression and/or activation of ASK1, and to date,strategies aimed at modulating ASK1 function have involved the use ofantibodies, dominant negative and dominant active mutants of theprotein.

U.S. Pat. No. 5,981,265 and U.S. Pat. No. 6,074,861 claim methods forregulating MAP3K protein activity in a cell by transforming ortransfecting the cell with a nucleic acid that is capable of hybridizingunder stringent conditions to a nucleic acid molecule encoding MAP3K1,MAP3K2, MAP3K3, MAP3K4, MAP3K5, and MAP3K6. Oligonucleotides for use inantisense, and triplex formation, as ribozymes, probes or primers and inother applications are generally disclosed. WO 01/07461 disclosesantisense compositions and methods for using the antisense compositionsto modulate the expression of MAP3K5 and treat diseases associated withexpression of MAP3K5.

Consequently, there remains a long felt need for agents capable ofeffectively modulating the activity of ASK1. A small molecule inhibitormay be proof to be an effective means for regulating ASK1 activities.

SUMMARY OF THE INVENTION

The present invention relates to compounds that have activity forinhibiting ASK1. The present invention also provides compositions,articles of manufacture and kits comprising these compounds. Inaddition, the invention relates to methods of making the compounds ofthe present invention, as well as intermediates useful in such methods.

In one aspect, the invention is directed to compounds having theformula:

wherein

N^(a) denotes a nitrogen atom;

ring A is selected from the group consisting of (C₃₋₁₂)alicyclyl,hetero(C₃₋₁₂)alicyclyl, (C₈₋₁₂)bicycloalicyclyl,hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₁)aryl,(C₇₋₁₂)bicycloaryl, and hetero(C₁₋₁₁)bicycloaryl, each unsubstituted orsubstituted with 1-5 substituents, where said 1-5 substituents of ring Aare each independently selected from the group consisting of halo,nitro, cyano, thio, oxy, oxo, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,aminocarbonyl, amino, carbonylamino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each unsubstituted or substituted;

X is selected from the group consisting of CR₃ and N;

R₁ is selected from the group consisting of hydrogen, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, amino, carbonylamino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each unsubsituted or substituted, or R₁ and R₂ are taken together toform a (C₃₋₆)cycloalkyl;

R₂ is selected from the group consisting of hydrogen, (C₁₋₆)alkoxy,carbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, (C₁₋₆)alkyl,(C₁₋₆)alkenyl, (C₁₋₆)alkynyl, hetero(C₁₋₆)alkyl, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, carbonyl(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl(C₁₋₃)alkyl,hetero(C₁₋₅)cycloalkyl(C₁₋₃)alkyl, (C₃₋₆)alicyclyl,hetero(C₁₋₅)alicyclyl, each substituted or unsubstituted; and

R₃ is selected from the group consisting of hydrogen, halo, nitro,cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,carbonylamino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each substituted or unsubstituted;

provided that

when X is N and ring A is a heteroalicyclyl, R₁ and R₂ are not bothhydrogen;

when X is CH, ring A is a five-membered heteroaryl, and one of R₁ and R₂is hydrogen, the other one of R₁ and R₂ is not an unsubstituted orsubstituted (C₁₋₄)alkyl; and

when X is CH, ring A is as defined above, and one of R₁ and R₂ is acarbonyl, the substituent on said carbonyl is selected from the groupconsisting of carbonyl, oxycarbonyl, aminocarbonyl, and unsubstituted orsubstituted cyclyl excluding cyclopropyl.

It is noted in regard to the above embodiment, the present invention isintended to encompass all pharmaceutically acceptable ionized forms(e.g., salts) and solvates (e.g., hydrates) of the compounds, regardlessof whether such ionized forms and solvates are specified since it iswell known in the art to administer pharmaceutical agents in an ionizedor solvated form. It is also noted that unless a particularstereochemistry is specified, recitation of a compound is intended toencompass all possible stereoisomers (e.g., enantiomers or diastereomersdepending on the number of chiral centers), independent of whether thecompound is present as an individual isomer or a mixture of isomers.Further, unless otherwise specified, recitation of a compound isintended to encompass all possible resonance forms and tautomers. Withregard to the claims, the language “compound comprising the formula,”“compound having the formula” and “compound of the formula” is intendedto encompass the compound and all pharmaceutically acceptable ionizedforms and solvates, all possible stereoisomers, and all possibleresonance forms and tautomers unless otherwise specifically specified inthe particular claim.

In another aspect, the invention is directed to pharmaceuticalcompositions that comprise an ASK1 inhibitor according to the presentinvention as an active ingredient. Pharmaceutical compositions accordingto the invention may optionally comprise 0.001%-100% of one or moreinhibitors of this invention. These pharmaceutical compositions may beadministered or coadministered by a wide variety of routes, includingfor example, orally, parenterally, intraperitoneally, intravenously,intraarterially, transdermally, sublingually, intramuscularly, rectally,transbuccally, intranasally, liposomally, via inhalation, vaginally,intraoccularly, via local delivery (for example by catheter or stent),subcutaneously, intraadiposally, intraarticularly, or intrathecally. Thecompositions may also be administered or coadministered in slow releasedosage forms.

In another aspect, the invention is directed to kits and articles ofmanufacture for treating disease states associated with ASK1.

In one embodiment, the kit comprises a composition comprising at leastone ASK1 inhibitor of the present invention in combination withinstructions. The instructions may indicate the disease state for whichthe composition is to be administered, storage information, dosinginformation and/or instructions regarding how to administer thecomposition. The kit may also comprise packaging materials. Thepackaging material may comprise a container for housing the composition.The kit may also optionally comprise additional components, such assyringes for administration of the composition. The kit may comprise thecomposition in single or multiple dose forms.

In another aspect, the invention is directed to articles of manufacturethat comprise a composition comprising at least one ASK1 inhibitor ofthe present invention in combination with packaging materials. Thepackaging material may comprise a container for housing the composition.The container may optionally comprise a label indicating the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The article of manufacture may alsooptionally comprise additional components, such as syringes foradministration of the composition. The article of manufacture maycomprise the composition in single or multiple dose forms.

In yet another aspect of the invention is directed to methods forpreparing compounds, compositions, kits, and articles of manufactureaccording to the present invention. For example, several syntheticschemes are provided herein for synthesizing compounds according to thepresent invention.

In yet other aspect, the invention is directed to methods of usingcompounds, compositions, kits and articles of manufacture according tothe present invention.

In one embodiment, the compounds, compositions, kits and articles ofmanufacture are used to inhibit ASK1.

In another embodiment, the compounds, compositions, kits and articles ofmanufacture are used to treat a disease state for which ASK1 possessactivity that contributes to the pathology and/or symptomology of thedisease state.

In another embodiment, a compound is administered to a subject whereinASK1 activity within the subject is altered, preferably reduced.

In another embodiment, a prodrug of a compound is administered to asubject that is converted to the compound in vivo where it inhibitsASK1.

In another embodiment, a method of inhibiting ASK1 is provided thatcomprises contacting an ASK1 with a compound according to the presentinvention.

In another embodiment, a method of inhibiting ASK1 is provided thatcomprises causing a compound according to the present invention to bepresent in a subject in order to inhibit ASK1 in vivo.

In another embodiment, a method is provided for using a compoundaccording to the present invention in order to manufacture a medicamentfor use in the treatment of a disease state that is known to be mediatedby ASK1, or that is known to be treated by ASK1 inhibitors.

It is noted that in the various methods of using the compounds of thepresent invention are intended, regardless of whether prodrug deliveryis specified, to encompass the administration of a prodrug that isconverted in vivo to a compound according to the present invention. Itis also noted that certain compounds of the present invention may bealtered in vivo prior to inhibiting ASK1 and thus may themselves beprodrugs for another compound. Such prodrugs of another compound may ormay not themselves independently have ASK1 inhibitory activity.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates SEQ ID NO:1 and SEQ ID NO: 2 referred to in thisapplication.

DEFINITION

Unless otherwise stated, the following terms used in the specificationand claims shall have the following meanings for the purposes of thisApplication.

It is noted that, as used in the specification and the appended claims,the singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise. Further, definitions of standardchemistry terms may be found in reference works, including Carey andSundberg “ADVANCED ORGANIC CHEMISTRY 5^(th) ED.” Vols. A (2007) and B(2007), Springer Science and Business Media, New York. Also, unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology, within the skill of the art are employed.

“Alicyclyl” means a cyclic radical that may be saturated or partiallyunsaturated with one, two or more double or triple bonds. Alicyclyl asdefined in this Application include monocyclic or polycyclic radicals,where the ring atoms of a monocyclic alicyclyl are all carbon atoms, andthe ring atoms of the cycle which is part of the polycyclic alicyclyland through which the polycyclic radical attaches to the parent moleculeare all carbon atoms. It is noted that alicyclyl encompasses cycloalkyl.(C_(X))alicyclyl and (C_(X-Y))alicyclyl are typically used where X and Yindicate the number of carbon atoms in the ring assembly. Examples ofalicyclic moieties include, but are not limited to, cyclopropyl,cyclohexane, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl,cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl,cycloheptadienyl, cyclooctanyl, cyclooctenyl, cyclooctadienyl,inden-1-yl, inden-6-yl, fluorin-1-yl, fluroin-9-yl,2,3-dihydroquinolin-6-yl, decalin, norbornene, norbornadiene, and thelike.

“Aliphatic” means a moiety characterized by a straight or branched chainarrangement of constituent carbon atoms and may be saturated orpartially unsaturated with one, two or more double or triple bonds.

“Alkenyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon double bond (—CR═CR′— or —CR═CR′R″, wherein R,R′ and R″ are each independently hydrogen or further substituents).Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl,hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and thelike. In particular embodiments, “alkenyl,” either alone or representedalong with another radical, can be a (C₂₋₂₀)alkenyl, a (C₂₋₁₅)alkenyl, a(C₂₋₁₀)alkenyl, a (C₂₋₅)alkenyl or a (C₂₋₃)alkenyl. Alternatively,“alkenyl,” either alone or represented along with another radical, canbe a (C₂)alkenyl, a (C₃)alkenyl or a (C₄)alkenyl.

“Alkenylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon double bonds (—CR═CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkenylene include ethene-1,2-diyl, propene-1,3-diyl,methylene-1,1-diyl, and the like. In particular embodiments,“alkenylene,” either alone or represented along with another radical,can be a (C₂₋₂₀) alkenylene, a (C₂₋₁₅) alkenylene, a (C₂₋₁₀) alkenylene,a (C₂₋₅) alkenylene or a (C₂₋₃) alkenylene. Alternatively, “alkenylene,”either alone or represented along with another radical, can be a (C₂)alkenylene, a (C₃) alkenylene or a (C₄) alkenylene.

“Alkoxy” means an oxygen moiety having a further alkyl substituent. Thealkoxy groups of the present invention can be optionally substituted.

“Alkyl” represented by itself means a straight or branched, saturated,aliphatic radical having a chain of carbon atoms, optionally with one ormore of the carbon atoms being replaced with oxygen (See “oxaalkyl”), acarbonyl group (See “oxoalkyl”), sulfur (See “thioalkyl”), and/ornitrogen (See “azaalkyl”). (C_(X))alkyl and (C_(X-Y))alkyl are typicallyused where X and Y indicate the number of carbon atoms in the chain. Forexample, (C₁₋₆)alkyl includes alkyls that have a chain of between 1 and6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, pentyl, hexyl, and the like). Alkyl representedalong with another radical (e.g., as in arylalkyl, heteroarylalkyl andthe like) means a straight or branched, saturated aliphatic divalentradical having the number of atoms indicated or when no atoms areindicated means a bond (e.g., (C₆₋₁₀)aryl(C₁₋₃)alkyl includes, benzyl,phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl,2-pyridinylmethyl and the like). In particular embodiments, “alkyl,”either alone or represented along with another radical, can be a(C₁₋₂₀)alkyl, a (C₁₋₁₅)alkyl, a (C₁₋₁₀)alkyl, a (C₁₋₅)alkyl or a(C₁₋₃)alkyl. Alternatively, “alkyl,” either alone or represented alongwith another radical, can be a (C₁)alkyl, a (C₂)alkyl or a (C₃)alkyl.

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated or unsaturated, aliphatic divalent radical. (C_(X))alkyleneand (C_(X-Y))alkylene are typically used where X and Y indicate thenumber of carbon atoms in the chain. For example, (C₁₋₆)alkyleneincludes methylene (—CH₂—), ethylene (—CH₂CH₂—), trimethylene(—CH₂CH₂CH₂—), tetramethylene (—CH₂CH₂CH₂CH₂—), 2-methyltetramethylene(—CH₂CH(CH₃)CH₂CH₂—), pentamethylene (—CH₂CH₂CH₂CH₂CH₂—), and the like.In particular embodiments, “alkylene,” either alone or represented alongwith another radical, can be a (C₁₋₂₀)alkylene, a (C₁₋₁₅)alkylene, a(C₁₋₁₀)alkylene, a (C₁₋₅)alkylene or a (C₁₋₃)alkylene. Alternatively,“alkylene,” either alone or represented along with another radical, canbe a (C₁)alkylene, a (C₂)alkylene or a (C₃)alkylene.

“Alkylidene” means a straight or branched, saturated, aliphatic radicalconnected to the parent molecule by a double bond. (C_(X))alkylidene and(C_(X-Y))alkylidene are typically used where X and Y indicate the numberof carbon atoms in the chain. For example, (C₁₋₆)alkylidene includesmethylidene (═CH₂), ethylidene (═CHCH₃), isopropylidene (═C(CH₃)₂),propylidene (═CHCH₂CH₃), allylidene (═CH—CH═CH₂), and the like. Inparticular embodiments, “alkylidene,” either alone or represented alongwith another radical, can be a (C₁₋₂₀)alkylidene, a (C₁₋₁₅)alkylidene, a(C₁₋₁₀)alkylidene, a (C₁₋₅)alkylidene or a (C₁₋₃)alkylidene.Alternatively, “alkylidene,” either alone or represented along withanother radical, can be a (C₁)alkylidene, a (C₂)alkylidene or a(C₃)alkylidene.

“Alkynyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon triple bond (—C≡C— or —C≡CR, wherein R ishydrogen or a further substituent). Examples of alkynyl include ethynyl,propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. In particularembodiments, “alkynyl,” either alone or represented along with anotherradical, can be a (C₂₋₂₀)alkynyl, a (C₂₋₁₅)alkynyl, a (C₂₋₁₀)alkynyl, a(C₂₋₅)alkynyl or a (C₂₋₃)alkynyl. Alternatively, “alkynyl,” either aloneor represented along with another radical, can be a (C₂)alkynyl, a(C₃)alkynyl or a (C₄)alkynyl.

“Alkynylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon triple bonds (—CR≡CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkynylene include ethyne-1,2-diyl, propyne-1,3-diyl, and the like. Inparticular embodiments, “alkynylene,” either alone or represented alongwith another radical, can be a (C₂₋₂₀) alkynylene, a (C₂₋₁₅) alkynylene,a (C₂₋₁₀) alkynylene, a (C₂₋₅) alkynylene or a (C₂₋₃) alkynylene.Alternatively, “alkynylene,” either alone or represented along withanother radical, can be a (C₂) alkynylene, a (C₃) alkynylene or a (C₄)alkynylene.

“Amido” means the radical —NR—C(═O)— and/or —NR—C(═O)R′, wherein each Rand R′ are independently hydrogen or a further substituent.

“Amino” means a nitrogen moiety having two further substituents where,for example, a hydrogen or carbon atom is attached to the nitrogen. Forexample, representative amino groups include —NH₂, —NHCH₃, —N(CH₃)₂,—NH((C₁₋₁₀)alkyl), —N((C₁₋₁₀)alkyl)₂, —NH(aryl), —NH(heteroaryl),—N(aryl)₂, —N(heteroaryl)₂, and the like. It is further understood thatthe two substituents may not be taken together with the nitrogen towhich the substituents are attached to form a ring. Unless indicatedotherwise, the compounds of the invention containing amino moieties mayinclude protected derivatives thereof. Suitable protecting groups foramino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl,and the like.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated ring system, where all ring atoms are in continuous pi (π)bonding and the total number of π electrons is equal to 4n+2. Anaromatic ring may be such that the ring atoms are only carbon atoms ormay include carbon and non-carbon atoms (See “heteroaryl”). Examples ofall carbon aromatic rings include benzene, naphthalene and anthracene,and the like. Examples of heteo-aromatic rings include pyrrole,thiophene, furan, oxazole, thiazole, imidazole, pyrazole, isoxazole,isothiazole, 1,2,3-oxadiazole, 1,2,3-triazole, 1,3,4-thiadiazole,pyridine, pyrimidine, pyrazine, 1,3,5-triazine, infolizine, indole,isoindole, benzo[b]furan, benzo[b]thiophene, benzimidazole,benzthiazole, purine, quinoline, isoquinoline, cinnoline, phthalazine,quinazoline, quinoxaline, 1,8-naphthyridine, pteridine, acridine,phenazine, and the like.

“Aryl” means a monocyclic or polycyclic radical, wherein each ring isaromatic or when fused with one or more rings forms an aromatic ringassembly. When the aryl is monocylic, the ring atoms are all carbonatoms, and when the aryl is polycyclic, the ring atoms of a ring whichis a component of the polycyclic radical and through which thepolycyclic radical attaches to the parent molecule are all carbon atoms.Examples of aryl include phenyl, naphthalenyl, anthracenyl,acridin-2-yl, quinolin-6-yl, benzo[b]furan-5-yl, and the like.(C_(X))aryl and (C_(X-Y))aryl are typically used where X and Y indicatethe number of carbon atoms in the ring. In particular embodiments,“aryl,” either alone or represented along with another radical, can be a(C₃₋₁₄)aryl, a (C₃₋₁₀)aryl, a (C₃₋₇)aryl, a (C₈₋₁₀)aryl or a (C₅₋₇)aryl.Alternatively, “aryl,” either alone or represented along with anotherradical, can be a (C₅)aryl, a (C₆)aryl, a (C₇)aryl, a (C₈)aryl, a(C₉)aryl or a (C₁₀)aryl.

“Azaalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with substitutedor unsubstituted nitrogen atoms (—NR— or —NRR′, wherein R and R′ areeach independently hydrogen or further substituents). For example, a(C₁₋₁₀)azaalkyl refers to a chain comprising between 1 and 10 carbonsand one or more nitrogen atoms.

“Aza-cyclyl” means a heterocyclyl moiety containing at least onenitrogen atom and the point of attachment of the cyclyl is through thenitrogen atom.

“Bicycloalicyclyl” refers to a bicyclic radical comprising two fused,spiro or bridged rings that may be saturated or partially unsaturatedwith one, two or more double or triple bonds, and the ring atoms of thering through which the bicyclic radical attaches to the parent moleculeare all carbon atoms. Examples of bicycloalicyclyl include inden-5-yl,indolin-5-yl, 4,5-dihydrobenzo[b]thiophen-5-yl, and the like.

“Bicycloalkyl” refers to a saturated bicyclic radical comprising twofused, spiro or bridged rings, where the ring atoms of the ring throughwhich the bicyclic radical attaches to the parent molecule are allcarbon atoms. In particular embodiments, “bicycloalkyl,” either alone orrepresented along with another radical, can be a (C₄₋₁₅)bicycloalkyl, a(C₄₋₁₀)bicycloalkyl, a (C₆₋₁₀)bicycloalkyl, or a (C₈₋₁₀)bicycloalkyl.Alternatively, “bicycloalkyl,” either alone or represented along withanother radical, can be a (C₈)bicycloalkyl, a (C₉)bicycloalkyl or a(C₁₀)bicycloalkyl. Examples of bicycloalkyl includedecahydronaphthalen-2-yl, octahydro-1H-inden-1-yl,decahydroquinolin-6-yl, octahydro-1H-indol-5-yl, and the like.

“Bicycloaryl” refers to an aromatic bicyclic radical comprising twofused, spiro or bridged rings, where both rings comprising the radicalare aromatic rings, and where the ring atoms of the ring through whichthe radical attaches to the parent molecule are all carbon atoms.(C_(X))bicycloaryl and (C_(X-Y))bicycloaryl are typically used where Xand Y indicate the number of carbon atoms in the bicyclic ring assemblyand directly attached to the ring. In particular embodiments,“bicycloaryl,” either alone or represented along with another radical,can be a (a (C₄₋₁₅)bicycloaryl, a (C₄₋₁₀)bicycloaryl, a(C₆₋₁₀)bicycloaryl or a (C₈₋₁₀)bicycloaryl. Alternatively,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₈)bicycloaryl, a (C₉)bicycloaryl or a (C₁₀)bicycloaryl.Examples of bicycloaryl include naphthalenyl, quinolin-6-yl,quinoxalin-6-yl, benzimidazol-5-yl, indol-5-yl, and the like.

“Bridging ring” and “bridged ring” as used herein refer to a ring thatis bonded to another ring to form a compound having a bicyclic orpolycyclic structure where two ring atoms that are common to both ringsare not directly bound to each other. Non-exclusive examples of commoncompounds having a bridging ring include borneol, norbornane,7-oxabicyclo[2.2.1]heptane, and the like. One or both rings of thebicyclic system may also comprise heteroatoms.

“Carbamoyl” means the radical —OC(O)NRR′, wherein R and R′ are eachindependently hydrogen or further substituents.

“Carbocyclic” or “carbocyclyl” refers to a monocyclic or polycyclicradical where all the ring atoms are carbon atoms.

“Carbonyl” means the radical —C(═O)— and/or —C(═O)R, wherein R ishydrogen or a further substituent. It is noted that the carbonyl radicalmay be further substituted with a variety of substituents to formdifferent carbonyl groups including acids, acid halides, aldehydes,amides, esters, and ketones.

“Carboxamido” means the radical —C(═O)—NR— and/or —C(═O)—NRR′, whereineach R and R′ are independently hydrogen or a further substituent.

“Carboxy” means the radical —C(═O)—O— and/or —C(═O)—OR, wherein R ishydrogen or a further substituent. It is noted that compounds of theinvention containing carboxy moieties may include protected derivativesthereof, i.e., where the oxygen is substituted with a protecting group.Suitable protecting groups for carboxy moieties include benzyl,tert-butyl, and the like.

“Cyano” means the radical —CN.

“Cycloalkyl” refers to a saturated, monocyclic or polycyclic radical,where the ring atoms of a monocyclic radical are all carbon atoms, andthe ring atoms of a ring that is a component of the polycyclic radicaland through which the radical attaches to the parent molecule are allcarbon atoms. (C_(X))cycloalkyl and (C_(X-Y))cycloalkyl are typicallyused where X and Y indicate the number of carbon atoms in the ringassembly. For example, (C₃₋₁₀)cycloalkyl includes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.2]octyl,adamantan-1-yl, octahydro-1H-inden-2-yl, decahydronaphthyl,oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,2-oxobicyclo[2.2.1]hept-1-yl, octahydro-1H-indol-5-yl,decahydroquinolinyl, and the like. In particular embodiments,“cycloalkyl,” either alone or represented along with another radical,can be a (C₃₋₁₄)cycloalkyl, a (C₃₋₁₀)cycloalkyl, a (C₃₋₇)cycloalkyl, a(C₈₋₁₀)cycloalkyl or a (C₅₋₇)cycloalkyl. Alternatively, “cycloalkyl,”either alone or represented along with another radical, can be a(C₅)cycloalkyl, a (C₆)cycloalkyl, a (C₇)cycloalkyl, a (C₈)cycloalkyl, a(C₉)cycloalkyl or a (C₁₀)cycloalkyl.

“Cycloalkylene” refers to a divalent cycloalkyl as defined in thisApplication. (C_(X))cycloalkylene and (C_(X-Y))cycloalkylene aretypically used where X and Y indicate the number of carbon atoms in thering assembly. In particular embodiments, “cycloalkylene,” either aloneor represented along with another radical, can be a(C₃₋₁₄)cycloalkylene, a (C₃₋₁₀)cycloalkylene, a (C₃₋₇)cycloalkylene, a(C₈₋₁₀)cycloalkylene or a (C₅₋₇)cycloalkylene. Alternatively,“cycloalkylene,” either alone or represented along with another radical,can be a (C₅)cycloalkylene, a (C₆)cycloalkylene, a (C₇)cycloalkylene, a(C₈)cycloalkylene, a (C₉)cycloalkylene or a (C₁₀)cycloalkylene.

“Cyclyl” and “cyclic” refers to a radical comprising a continuous arrayof atoms. Cyclyl and cyclic as defined herein may be monocyclic,bicyclic or polycyclic, and include fused, spiro, or bridgedpolycyclics, and each of the cyclic components may be aromatic,partially unsaturated, or saturated, and the ring atoms are all carbonatoms or optionally one or more of the ring atoms are heteroatoms.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“EC₅₀” means the molar concentration of an agonist that produces 50% ofthe maximal possible effect of that agonist. The action of the agonistmay be stimulatory or inhibitory.

“Fused ring” as used herein refers to a ring that is bonded to anotherring to form a compound having a bicyclic or polycyclic structure wherethe ring atoms that are common to both rings are directly bound to eachother. Non-exclusive examples of common fused rings include decalin,naphthalene, anthracene, phenanthrene, indole, furan, benzofuran,quinoline, and the like. Compounds having fused ring systems may besaturated, partially saturated, carbocyclics, heterocyclics, aromatics,heteroaromatics, and the like.

“Halo” means fluoro, chloro, bromo or iodo.

“Heteroalkyl” means alkyl, as defined in this Application, provided thatone or more of the atoms within the alkyl chain is a heteroatom. Inparticular embodiments, “heteroalkyl,” either alone or represented alongwith another radical, can be a hetero(C₁₋₂₀)alkyl, a hetero(C₁₋₁₅)alkyl,a hetero(C₁₋₁₀)alkyl, a hetero(C₁₋₅)alkyl, a hetero(C₁₋₃)alkyl or ahetero(C₁₋₂)alkyl. Alternatively, “heteroalkyl,” either alone orrepresented along with another radical, can be a hetero(C₁)alkyl, ahetero(C₂)alkyl or a hetero(C₃)alkyl.

“Heteroalicyclyl” or “heterocyclic” means an alicyclyl, as defined inthis Application, provided at least one of the ring atoms is aheteroatom such as nitrogen, oxygen and sulfur. The nitrogen atoms canbe optionally quaternerized or oxidized and the sulfur atoms can beoptionally oxidized. It is noted that heteroalicycle encompassesheterocycloalkyl. (C_(X))heteroalicyclyl and hetero(C_(X-Y))alicyclylare typically used where X and Y indicate the number of carbon atoms inthe ring assembly. Examples of heteroalicyclyl include pyrroline,imidazoline, pyrazoline, pyran, indene, indoline, fluorine, and thelike.

“Heteroaryl” refers to an aryl as defined in this Application providedthat at least one of the ring atoms of the ring through which theheteroaryl attaches to the parent molecule is a heteroatom. Monocyclicheteroaryl groups include, but are not limited to, cyclic aromaticgroups having five or six ring atoms, wherein at least one ring atom isa heteroatom and the remaining ring atoms are carbon. The nitrogen atomscan be optionally quaternerized and the sulfur atoms can be optionallyoxidized. Heteroaryl groups of this Application include, but are notlimited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolyl, 1,2,3-oxadiazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolinyl, thiazolyl, 1,3,4-thiadiazolyl,triazolyl and tetrazolyl. “Bicyclic or tricyclic heteroaryls” include,but are not limited to, benzo[b]furan-3-yl, benzo[b]thiophen-3-yl,benzimidazol-2-yl, imidazo[4,5-c]pyridinyl, quinazolin-2-yl, and thelikes. The heteroaryl groups of this invention can be substituted orunsubstituted. In particular embodiments, “heteroaryl,” either alone orrepresented along with another radical, can be a hetero(C₁₋₁₃)aryl, ahetero(C₂₋₁₃)aryl, a hetero(C₂₋₆)aryl, a hetero(C₃₋₉)aryl or ahetero(C₅₋₉)aryl. Alternatively, “heteroaryl,” either alone orrepresented along with another radical, can be a hetero(C₃)aryl, ahetero(C₄)aryl, a hetero(C₅)aryl, a hetero(C₆)aryl, a hetero(C₇)aryl, ahetero(C₈)aryl or a hetero(C₉)aryl.

“Heteroatom” refers to an atom that is not a carbon atom. Particularexamples of heteroatoms include, but are not limited to, nitrogen,oxygen, and sulfur.

“Heteroatom moiety” includes a moiety where the atom by which the moietyis attached is not a carbon. Examples of heteroatom moieties include—NR—, —N⁺(═O⁻)—, —O—, —S— or —S(O)₂—, wherein R is hydrogen or a furthersubstituent.

“Heterobicycloalicyclyl” refers to a bicycloalicyclyl radical as definedin this Application provided that at least one of the ring atoms of thering through which the heterobicycloalicyclic radical attaches to theparent molecule is a heteroatom.

“Heterobicycloalkyl” means a bicycloalkyl radical as defined in thisApplication, provided that at least one of the ring atoms of the ringthat is a component of the bicyclic radical and through which theheterocycloalkyl ring assembly attaches is a heteroatom. For examplehetero(C₉₋₁₂)bicycloalkyl as used in this application includes, but isnot limited to, 3-aza-bicyclo[4.1.0]hept-3-yl,2-aza-bicyclo[3.1.0]hex-2-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, and thelike. In particular embodiments, “heterobicycloalkyl,” either alone orrepresented along with another radical, can be ahetero(C₁₋₁₄)bicycloalkyl, a hetero(C₄₋₁₄)bicycloalkyl, ahetero(C₄₋₉)bicycloalkyl or a hetero(C₅₋₉)bicycloalkyl. Alternatively,“heterobicycloalkyl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloalkyl, hetero(C₆)bicycloalkyl,hetero(C₇)bicycloalkyl, hetero(C₈)bicycloalkyl or ahetero(C₉)bicycloalkyl.

“Heterobicycloaryl” means a bicycloaryl radical as defined in thisApplication, provided that at least one of the ring atoms of the ringwhich is a component of the bicyclic radical and through which theheterobicycloaryl radical attaches to the parent atom is a heteroatom.For example, hetero(C₄₋₁₂)bicycloaryl as used in this Applicationincludes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl,quinolin-2-yl, and the like. In particular embodiments,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₄)bicycloaryl, a hetero(C₄₋₁₄)bicycloaryl,a hetero(C₄₋₉)bicycloarylor a hetero(C₅₋₉)bicycloaryl. Alternatively,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloaryl, hetero(C₆)bicycloaryl,hetero(C₇)bicycloaryl, hetero(C₈)bicycloaryl or a hetero(C₉)bicycloaryl.

“Heterocycloalkyl” means a cycloalkyl radical as defined in thisApplication, provided that at least one of the ring atoms of the ringthrough which the heterocycloalkyl radical attaches to the parent atomis a heteroatom. The heteroatom is independently selected from N, O, orS. Non-exclusive examples of heterocycloalkyl include piperidyl,4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl,1,2-pyrazolidin-4-yl, 1,3-dioxanyl, 1,4-dioxoianyl and the like. Inparticular embodiments, “heterocycloalkyl,” either alone or representedalong with another radical, can be a hetero(C₁₋₁₃)cycloalkyl, ahetero(C₁₋₉)cycloalkyl, a hetero(C₁₋₆)cycloalkyl, ahetero(C₅₋₉)cycloalkyl or a hetero(C₂₋₆)cycloalkyl. Alternatively,“heterocycloalkyl,” either alone or represented along with anotherradical, can be a hetero(C₂)cycloalkyl, a hetero(C₃)cycloalkyl, ahetero(C₄)cycloalkyl, a hetero(C₅)cycloalkyl, a hetero(C₆)cycloalkyl,hetero(C₇)cycloalkyl, hetero(C₈)cycloalkyl or a hetero(C₉)cycloalkyl.

“Heterocycloalkylene” means a divalent heterocycloalkyl, wherein theheterocycloalkyl is as defined in this Application. In particularembodiments, “heterocycloalkylene,” either alone or represented alongwith another radical, can be a hetero(C₁₋₁₃)cycloalkylene, ahetero(C₁₋₉)cycloalkylene, a hetero(C₁₋₆)cycloalkylene, ahetero(C₅₋₉)cycloalkylene or a hetero(C₂₋₆)cycloalkylene. Alternatively,“heterocycloalkylene,” either alone or represented along with anotherradical, can be a hetero(C₂)cycloalkylene, a hetero(C₃)cycloalkylene, ahetero(C₄)cycloalkylene, a hetero(C₅)cycloalkylene, ahetero(C₆)cycloalkylene, hetero(C₇)cycloalkylene,hetero(C₈)cycloalkylene or a hetero(C₉)cycloalkylene.

“Heterocyclyl” means a cyclyl as defined in this Application providedthat at least one of the ring atoms is a heteroatom.

“Hydroxy” means the radical —OH.

“IC₅₀” means the molar concentration of an inhibitor that produces 50%inhibition of the target enzyme.

“Imino” means the radical —CR(═NR′) and/or —C(═NR′)—, wherein R and R′are each independently hydrogen or a further substituent.

“Iminoketone derivative” means a derivative comprising the moiety—C(NR)—, wherein R is hydrogen or a further substituent.

“Isomers” means compounds having identical molecular formulae butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers.”Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers.” A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter.” A compound with one chiral center has two enantiomeric forms ofopposite chirality. A mixture of the two enantiomeric forms is termed a“racemic mixture.” A compound that has more than one chiral center has2^(n−1) enantiomeric pairs, where n is the number of chiral centers.Compounds with more than one chiral center may exist as ether anindividual diastereomer or as a mixture of diastereomers, termed a“diastereomeric mixture.” When one chiral center is present astereoisomer may be characterized by the absolute configuration of thatchiral center. Absolute configuration refers to the arrangement in spaceof the substituents attached to the chiral center. Enantiomers arecharacterized by the absolute configuration of their chiral centers anddescribed by the R- and S-sequencing rules of Cahn, Ingold and Prelog.Conventions for stereochemical nomenclature, methods for thedetermination of stereochemistry and the separation of stereoisomers arewell known in the art (e.g., see “Advanced Organic Chemistry”, 5thedition, March, Jerry, John Wiley & Sons, New York, 2001).

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under reaction (e.g., alkylating) conditions.Examples of leaving groups include, but are not limited to, halo (e.g.,F, Cl, Br and I), alkyl (e.g., methyl and ethyl) and sulfonyloxy (e.g.,mesyloxy, ethanesulfonyloxy, benzenesulfonyloxy and tosyloxy),thiomethyl, thienyloxy, dihalophosphinoyloxy, tetrahalophosphoxy,benzyloxy, isopropyloxy, acyloxy, and the like.

“Nitro” means the radical —NO₂.

“Oxaalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with oxygen atoms(—O— or —OR, wherein R is hydrogen or a further substituent). Forexample, an oxa(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more oxygen atoms.

“Oxoalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with carbonylgroups (—C(═O)— or —C(═O)—R, wherein R is hydrogen or a furthersubstituent). The carbonyl group may be an aldehyde, ketone, ester,amide, acid, or acid halide. For example, an oxo(C₁₋₁₀)alkyl refers to achain comprising between 1 and 10 carbon atoms and one or more carbonylgroups.

“Oxy” means the radical —O— or —OR, wherein R is hydrogen or a furthersubstituent. Accordingly, it is noted that the oxy radical may befurther substituted with a variety of substituents to form different oxygroups including hydroxy, alkoxy, aryloxy, heteroaryloxy or carbonyloxy.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of thepresent invention which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as aceticacid, propionic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonicacid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

“Polycyclic ring” includes bicyclic and multi-cyclic rings. Theindividual rings comprising the polycyclic ring can be fused, spiro orbridging rings.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an inhibitor according to the present invention. The prodrug itselfmay or may not also have activity with respect to a given targetprotein. For example, a compound comprising a hydroxy group may beadministered as an ester that is converted by hydrolysis in vivo to thehydroxy compound. Suitable esters that may be converted in vivo intohydroxy compounds include acetates, citrates, lactates, phosphates,tartrates, malonates, oxalates, salicylates, propionates, succinates,fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates,isethionates, di-p-toluoyltartrates, methanesulfonates,ethanesulfonates, benzenesulfonates, p-toluenesulfonates,cyclohexylsulfamates, quinates, esters of amino acids, and the like.Similarly, a compound comprising an amine group may be administered asan amide that is converted by hydrolysis in vivo to the amine compound.

“Protected derivatives” means derivatives of inhibitors in which areactive site or sites are blocked with protecting groups. Protectedderivatives are useful in the preparation of inhibitors or in themselvesmay be active as inhibitors. A comprehensive list of suitable protectinggroups can be found in P. G. M. Wuts and T. W. Greene, “Greene'sProtecting Groups in Organic Synthesis, 4th edition, John Wiley & Sons,Inc. 2007.

“Ring” and “ring assembly” refers to a continuous link of atoms. Theatoms in this continuous link (the ring atoms) may be all carbon atoms(carbocyclyl), or may optionally contain heteroatoms (heterocyclyl). Thering system may be aromatic and non-aromatic, monocyclic, bicyclic orpolycyclic. In addition, for bicyclic and polycyclic systems, theindividual rings comprising the polycyclic ring can be fused, spiro orbridging rings.

“Subject” and “patient” includes humans, non-human mammals (e.g., dogs,cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like)and non-mammals (e.g., birds, and the like).

“Substituted or unsubstituted” means that a given moiety may consist ofonly hydrogen substituents through available valencies (unsubstituted)or may further comprise one or more non-hydrogen substituents throughavailable valencies (substituted) that are not otherwise specified bythe name of the given moiety. For example, isopropyl is an example of anethylene moiety that is substituted by —CH₃. In general, a non-hydrogensubstituent may be any substituent that may be bound to an atom of thegiven moiety that is specified to be substituted. Examples ofsubstituents include, but are not limited to, aldehyde, alicyclic,aliphatic, (C₁₋₁₀)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl,aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl,carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo,heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl,heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl,and oxoalkyl moieties, each of which may optionally also be substitutedor unsubstituted. In one particular embodiment, examples of substituentsinclude, but are not limited to, hydrogen, halo, nitro, cyano, thio,oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,(C₁₋₁₀)azaalkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl. In addition, the substituent is itselfoptionally substituted by a further substituent. In one particularembodiment, examples of the further substituent include, but are notlimited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl.

“Sulfamoyl,” means the radical —OS(O)₂NRR′, wherein R and R′ are eachindependently hydrogen or further substituents.

“Sulfinyl” means the radical —SO— and/or —SO—R, wherein R is hydrogen ora further substituent. It is noted that the sulfinyl radical may befurther substituted with a variety of substituents to form differentsulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters,and sulfoxides.

“Sulfonamido” means the radical —S(O)₂—NR— and/or —S(O)₂—NRR′,—NR—S(O)₂— and/or —NR—S(O)₂R′, wherein each R and R′ are independentlyhydrogen or a further substituent.

“Sulfonyl” means the radical —SO₂— and/or —SO₂—R, wherein R is hydrogenor a further substituent. It is noted that the sulfonyl radical may befurther substituted with a variety of substituents to form differentsulfonyl groups including sulfonic acids, sulfonamides, sulfonateesters, and sulfones.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Thio” denotes replacement of an oxygen by a sulfur and includes, but isnot limited to, —SR, —S— and ═S containing groups.

“Thioalkyl” means an alkyl, as defined above, except where one or moreof the carbon atoms forming the alkyl chain are replaced with sulfuratoms (—S— or —S—R, wherein R is hydrogen or a further substituent). Forexample, a thio(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more sulfur atoms.

“Thiocarbonyl” means the radical —C(═S)— and/or —C(═S)—R, wherein R ishydrogen or a further substituent. It is noted that the thiocarbonylradical may be further substituted with a variety of substituents toform different thiocarbonyl groups including thioacids, thioamides,thioesters, and thioketones.

“Treatment” or “treating” means any administration of a compound of thepresent invention and includes:

-   (1) preventing the disease from occurring in an animal which may be    predisposed to the disease but does not yet experience or display    the pathology or symptomatology of the disease,-   (2) inhibiting the disease in an animal that is experiencing or    displaying the pathology or symptomatology of the diseased (i.e.,    arresting further development of the pathology and/or    symptomatology), or-   (3) ameliorating the disease in an animal that is experiencing or    displaying the pathology or symptomatology of the diseased (i.e.,    reversing the pathology and/or symptomatology).

It is noted in regard to all of the definitions provided herein that thedefinitions should be interpreted as being open ended in the sense thatfurther substituents beyond those specified may be included. Hence, a C₁alkyl indicates that there is one carbon atom but does not indicate whatare the substituents on the carbon atom. Hence, a (C₁)alkyl comprisesmethyl (i.e., —CH₃) as well as —CRR′R″ where R, R′, and R″ may eachindependently be hydrogen or a further substituent where the atomattached to the carbon is a heteroatom or cyano. Hence, CF₃, CH₂OH andCH₂CN, for example, are all (C₁)alkyls. Similarly, terms such asalkylamino and the like comprise dialkylamino and the like.

A compound having a formula that is represented with a dashed bond isintended to include the formulae optionally having zero, one or moredouble bonds, as exemplified and shown below:

In addition, atoms making up the compounds of the present invention areintended to include all isotopic forms of such atoms. Isotopes, as usedherein, include those atoms having the same atomic number but differentmass numbers. By way of general example and without limitation, isotopesof hydrogen include tritium and deuterium, and isotopes of carboninclude ¹³C and ¹⁴C.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that may be used to inhibitthe enzyme ASK1. The present invention also relates to pharmaceuticalcompositions, kits and articles of manufacture comprising suchcompounds. In addition, the present invention relates to methods andintermediates useful for making the compounds. Further, the presentinvention relates to methods of using said compounds.

It is noted that the compounds of the present invention may also possessactivity for other members of the same protein family and thus may beused to address disease states associated with these other familymembers.

Compounds of the Invention

In one of its aspects, the present invention relates to compounds thatare useful as ASK1 inhibitors.

In one embodiment, ASK1 inhibitors of the present invention arecompounds consisting the formula:

wherein

N^(a) denotes a nitrogen atom;

ring A is selected from the group consisting of (C₃₋₁₂)alicyclyl,hetero(C₃₋₁₂)alicyclyl, (C₈₋₁₂)bicycloalicyclyl,hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₁)aryl,(C₇₋₁₂)bicycloaryl, and hetero(C₁₋₁₁)bicycloaryl, each unsubstituted orsubstituted with 1-5 substituents, where said 1-5 substituents of ring Aare each independently selected from the group consisting of halo,nitro, cyano, thio, oxy, oxo, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,aminocarbonyl, amino, carbonylamino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each unsubstituted or substituted;

X is selected from the group consisting of CR₃ and N;

R₁ is selected from the group consisting of hydrogen, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, amino, carbonylamino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each unsubstituted or substituted, or R₁ and R₂ are taken together toform a (C₃₋₆)cycloalkyl;

R₂ is selected from the group consisting of hydrogen, (C₁₋₆)alkoxy,carbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, (C₁₋₆)alkyl,(C₁₋₆)alkenyl, (C₁₋₆)alkynyl, hetero(C₁₋₆)alkyl, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, carbonyl(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl(C₁₋₃)alkyl,hetero(C₁₋₅)cycloalkyl(C₁₋₃)alkyl, (C₃₋₆)alicyclyl, andhetero(C₁₋₅)alicyclyl, each substituted or unsubstituted; and

R₃ is selected from the group consisting of hydrogen, halo, nitro,cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,carbonylamino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₃₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each substituted or unsubstituted;

provided that

when X is N and ring A is a heteroalicyclyl, R₁ and R₂ are not bothhydrogen;

when X is CH, ring A is a five-membered heteroaryl, and one of R₁ and R₂is hydrogen, the other one of R₁ and R₂ is not an unsubstituted orsubstituted (C₁₋₄)alkyl; and

when X is CH, ring A is as defined above, and one of R₁ and R₂ is acarbonyl, the substituent on said carbonyl is selected from the groupconsisting of carbonyl, oxycarbonyl, aminocarbonyl, and unsubstituted orsubstituted cyclyl excluding cyclopropyl.

In another embodiment, ASK1 inhibitors of the present invention arecompounds consisting of the formula:

wherein

N^(a) denotes a nitrogen atom;

ring A is selected from the group consisting of (C₃₋₁₂)alicyclyl,hetero(C₃₋₁₂)alicyclyl, (C₈₋₁₂)bicycloalicyclyl,hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₁)aryl,(C₇₋₁₂)bicycloaryl, and hetero(C₁₋₁₁)bicycloaryl, each unsubstituted orsubstituted with 1-5 substituents, where said 1-5 substituents of ring Aare each independently selected from the group consisting of halo,nitro, cyano, thio, oxy, oxo, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,aminocarbonyl, amino, carbonylamino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each unsubstituted or substituted;

R₁ is selected from the group consisting of hydrogen, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, amino, carbonylamino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each unsubstituted or substituted, or R₁ and R₂ are taken together toform a (C₃₋₆)cycloalkyl;

R₂ is selected from the group consisting of hydrogen, (C₁₋₆)alkoxy,carbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, (C₁₋₆)alkyl,(C₁₋₆)alkenyl, (C₁₋₆)alkynyl, hetero(C₁₋₆)alkyl, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, carbonyl(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl(C₁₋₃)alkyl,hetero(C₁₋₅)cycloalkyl(C₁₋₃)alkyl, (C₃₋₆)alicyclyl, andhetero(C₁₋₅)alicyclyl, each substituted or unsubstituted; and

R₃ is selected from the group consisting of hydrogen, halo, nitro,cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,carbonylamino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each substituted or unsubstituted;

provided that

when X is CH, ring A is a five-membered heteroaryl, and one of R₁ and R₂is hydrogen, the other one of R₁ and R₂ is not an unsubstituted orsubstituted (C₁₋₄)alkyl; and

when X is CH, ring A is as defined above, and one of R₁ and R₂ is acarbonyl, the substituent on said carbonyl is selected from the groupconsisting of carbonyl, oxycarbonyl, aminocarbonyl, and unsubstituted orsubstituted cyclyl excluding cyclopropyl.

In yet another embodiment, the ASK1 inhibitors of the invention arecompounds of the formula

wherein

N^(a) denotes a nitrogen atom;

ring A is selected from the group consisting of (C₃₋₁₂)alicyclyl,hetero(C₃₋₁₂)alicyclyl, (C₈₋₁₂)bicycloalicyclyl,hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₁)aryl,(C₇₋₁₂)bicycloaryl, and hetero(C₁₋₁₁)bicycloaryl, each unsubstituted orsubstituted with 1-5 substituents, where said 1-5 substituents of ring Aare each independently selected from the group consisting of halo,nitro, cyano, thio, oxy, oxo, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,aminocarbonyl, amino, carbonylamino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each unsubstituted or substituted;

R₁ is selected from the group consisting of hydrogen, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, amino, carbonylamino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each unsubstituted or substituted, or R₁ and R₂ are taken together toform a (C₃₋₆)cycloalkyl;

R₂ is selected from the group consisting of hydrogen, (C₁₋₆)alkoxy,carbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, (C₁₋₆)alkyl,(C₁₋₆)alkenyl, (C₁₋₆)alkynyl, hetero(C₁₋₆)alkyl, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, carbonyl(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl(C₁₋₃)alkyl,hetero(C₁₋₅)cycloalkyl(C₁₋₃)alkyl, (C₃₋₆)alicyclyl, andhetero(C₁₋₅)alicyclyl, each substituted or unsubstituted; and

provided that

when ring A is a heteroalicyclyl, R₁ and R₂ are not both hydrogen.

R₁

The compound according to any one of the above embodiments andvariations, in some variations, R₁ is selected from the group consistingof (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl, (C₈₋₁₂)bicycloalicyclyl,hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted with 1-3 substituents that are each independently selectedfrom the group consisting of halo, nitro, cyano, hydroxy, oxo, thio,oxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, carbonylamino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,(C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl, (C₈₋₁₂)bicycloalicyclyl,hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted.

In some particular variations, R₁ is selected from the group consistingof (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each unsubstituted or substituted with the 1-3substituents of R₁.

In some variation of these particular variations, R₁ is selected fromthe group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiadiazolyl, phenyl, pyridinyl, pyridonyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, indolyl, isoindolyl, indolizinyl,benzimidazolyl, purinyl, naphthalenyl, quinolinyl, isoquinolinyl,cinnolinyl, phthalazinlyl, quinazolinyl, quinoxalinyl, naphthyridinyl,pteridinyl, pyrimidone, imidazolyl, and quinolinyl, each unsubstitutedor substituted with the 1-3 substituents of R₁. In other variations, R₁is selected from the group consisting of oxazolyl, isoxazolyl andoxadiazolyl, each unsubstituted or substituted with the 1-3 substituentsof R₁.

In other particular variations, R₁ is selected from the group consistingof (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl, (C₈₋₁₂)bicycloalicyclyl,hetero(C₃₋₁₁)bicycloalicyclyl, each unsubstituted or substituted withsaid 1-3 substituents of R₁. In some variations of these particularvariations, R₁ is selected from the group consisting of pyrrolidinyl,pyridonyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl,pyranyl, thiopyranyl, tetrahydrothiopyranyl, cyclohexyl, cyclopentyl,cyclohexenyl, and cyclopentenyl, each unsubstituted or substituted withthe 1-3 substituents of R₁. In still other variations of theseparticular variations, R₁ is selected from the group consisting ofpyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyranyl,thiopyranyl, tetrahydrothiopyranyl, and cyclohexyl, each unsubstitutedor substituted with the 1-3 substituents of R₁.

In all the above embodiments and particular variations, the 1-3substituents of R₁ are each independently selected from the groupconsisting of halo, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, carbonyl,oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,sulfonyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, andimino(C₁₋₁₀)alkyl, each unsubstituted or substituted. In somevariations, the 1-3 substituents of R₁ are independently selected fromthe group consisting of (C₁₋₁₀)alkyl, (C₁₋₁₀)alkoxy, hydroxy, andcarbonyloxy.

In all the above embodiments and variations above, in some specialvariations, R₁ is a substituted carbonyl of the formula —C(O)R₄, whereR₄ is as defined below.

In all the above embodiments and variations above, in some other specialvariations, R₁ is a substituted carbonyl of the formula —C(O)-ring B,where ring B is as defined below.

R₄

In one special variation, R₁ is a substituted carbonyl of the formula—C(O)R₄, wherein the compound is of the formula:

where

R₄ is selected from the group consisting of carbonyl, oxycarbonyl, andaminocarbonyl, each unsubstituted or substituted with 1-3 substituents,each of which is independently selected from the group consisting ofnitro, cyano, thio, mercapto, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, amino, amido, carboxamido,carbamoyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfamoyl, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each unsubstituted or substituted.

In another special variation of the above embodiments and variations, R₁is a substituted carbonyl of the formula —C(O)R₄, where the compound isof the formula:

where

R₄ is selected from the group consisting of carbonyl, oxycarbonyl, andaminocarbonyl, each unsubstituted or substituted with 1-3 substituents,each of which is independently selected from the group consisting ofnitro, cyano, thio, mercapto, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, amino, amido, carboxamido,carbamoyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfamoyl, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each unsubstituted or substituted.

Of the two special variations of the compounds of the invention above,in some variations, the 1-3 substituents of R₄ are each independentlyselected from the group consisting of (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl,(C₁₋₁₀)alkynyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, each unsubstituted or substituted.

In other variations, the 1-3 substituents of R₄ are each independentlyselected from the group consisting of (C₁₋₆)alkyl, (C₁₋₆)alkenyl,(C₁₋₆)alkynyl, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,(C₃₋₆)cycloalkyl(C₁₋₃)alkyl, hetero(C₃₋₆)cycloalkyl(C₁₋₃)alkyl,phenyl(C₁₋₃)alkyl, hetero(C₂₋₅)aryl(C₁₋₃)alkyl, (C₃₋₆)cycloalkyl,hetero(C₂₋₅)cycloalkyl, phenyl, and hetero(C₂₋₅)aryl, each unsubstitutedor substituted.

In still other variations, the 1-3 substituents of R₄ are eachindependently selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, hetero(C₂₋₅)cycloalkyl, phenyl, and hetero(C₂₋₅)aryl.

Ring B

In one particularly special variation of the above embodiments andvariations, R₁ is a substituted carbonyl of the formula —C(O)-ring B,where the compound is of the formula:

where

ring B is selected from the group consisting of (C₄₋₁₂)alicyclyl,hetero(C₃₋₁₁)alicyclyl, (C₈₋₁₂)bicycloalicyclyl,hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted with 1-3 substituents,

where

-   -   each of said 1-3 substituents of ring B is independently        selected from the group consisting of halo, nitro, cyano, thio,        mercapto, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        aminocarbonyl, amino, amido, carboxamido, carbamoyl,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        sulfamoyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,        (C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl,        (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and        hetero(C₄₋₁₂)bicycloaryl, each unsubstituted or substituted.

In another particularly special variation of the above embodiments andvariations, R₁ is a substituted carbonyl of the formula —C(O)-ring B,where the compound is of the formula:

where

ring B is selected from the group consisting of (C₄₋₁₂)alicyclyl,hetero(C₃₋₁₁)alicyclyl, (C₈₋₁₂)bicycloalicyclyl,hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted with 1-3 substituents,

where

-   -   each of said 1-3 substituents of ring B is independently        selected from the group consisting of halo, nitro, cyano, thio,        mercapto, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        aminocarbonyl, amino, amido, carboxamido, carbamoyl,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        sulfamoyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,        (C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl,        (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and        hetero(C₄₋₁₂)bicycloaryl, each unsubstituted or substituted.

The compounds of the above two particularly special variations, ring Bis selected from the group consisting of (C₄₋₁₂)alicyclyl,hetero(C₃₋₁₂)alicyclyl, (C₈₋₁₂)bicycloalicyclyl,hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₆)aryl, hetero(C₁₋₆)aryl,(C₈₋₁₀)bicycloaryl, and hetero(C₁₋₁₀)bicycloaryl, each unsubstituted orsubstituted with said 1-3 substituents of ring B.

In some variations, ring B is a five-membered heteroaryl containing upto four heteroatoms, where each of said four heteroatoms isindependently selected from the group consisting of nitrogen, oxygen andsulfur, and where the heteroaryl is unsubstituted or substituted withsaid 1-3 substituents of ring B. In some particular variations, ring Bis selected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, and thiadiazolyl, each unsubstituted orsubstituted with said 1-3 substituents of ring B. In other particularvariations, ring B is selected from the group consisting of a thiazolyl,isothiazolyl, furanyl, and theinyl, each unsubstituted or substitutedwith said 1-3 substituents of ring B. In more particular variations,ring B is a thienyl, unsubstituted or substituted with said 1-3substituents of ring B.

In other variations, ring B is a six-membered aryl or heteroaryl, wherethe heteroaryl contains up to four nitrogen atoms, and where the aryl orheteroaryl is unsubstituted or substituted with said 1-3 substituents ofring B. In some particular variations, ring B is selected from the groupconsisting of phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,and triazinyl, each unsubstituted or substituted with said 1-3substituents of ring B. In more particular variations, ring B is aphenyl, each unsubstituted or substituted with said 1-3 substituents. Inother more particular variations, ring B is a pyridinyl, eachunsubstituted or substituted with said 1-3 substituents of ring B.

In the variations that ring B is a six membered aryl, or a five or sixmembered heteroaryl, in some variations, when present, the 1-3substituents of ring B are independently selected from the groupconsisting of halo, nitro, oxy, hydroxy, (C₁₋₆)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, (C₁₋₆)alkyl, (C₁₋₆)alkenyl, (C₁₋₆)alkynyl,halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, aza(C₁₋₆)alkyl, oxa(C₁₋₆)alkyl,oxo(C₁₋₆)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₆)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₃₋₇)alicyclyl, hetero(C₃₋₇)alicyclyl,(C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, each unsubstituted or substituted.

In other variations, when present, the 1-3 substituents of ring B areeach independently selected from the group consisting of halo, hydroxyl,nitro, thio, cyano, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,halo(C₁₋₆)alkyl, (C₁₋₆)alkoxy, hydroxyl(C₁₋₆)alkyl, mercapto, sulfinyl,sulfonyl, sulfamoyl, amino, amido, carboxyamido, carbamoyl, carbonyl andcarbonyloxy, each unsubstituted or substituted.

In still other variations, when present, the 1-3 substituents of ring Bare independently selected from the group consisting of hydroxyl,(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, halo(C₁₋₆)alkyl,—C(CH₃)(OH)CF₃, (C₁₋₆)alkoxy, halo, cyano,

where

k is 1, 2, 3, or 4; and

R₂₁, in some variation is selected from the group consisting ofhydroxyl, (C₁₋₄)alkyl, (C₂₋₄)alkenyl, (C₂₋₄)alkynyl, halo(C₁₋₄)alkyl,alkyloxy, —(CH₂)_(n)OH, —CF₃, —(CH₂)_(n)CN, —(CH₂)_(n)COOH,—(CH₂)_(n)CONH₂, —(CH₂)_(n)heteroaryl, and—(CH₂)_(n)O(CH₂)_(n)heteroaryl, where n is 0, 1, 2, 3, or 4. In othervariations, R₂₁ is selected from the group consisting of methyl,perflurormethyl, hydroxyl(C₁₋₄)alkyl, hydroxyl, and cyano(C₁₋₄)alkyl.

The compounds of the above two particularly special variations, ring Bis an unsubstituted or substituted phenyl consisting of the formula

where

R₇, R₈, R₉, R₁₀, and R₁₁ are each independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, cyano, thio, (C₁₋₆)alkyl,halo(C₁₋₆)alkyl, (C₁₋₆)alkoxy, hydroxyl(C₁₋₆)alkyl, mercapto, sulfinyl,sulfonyl, sulfamoyl, amino, amido, carboxyamido, carbamoyl, carbonyl andcarboxyl, each unsubstituted or substituted; provided that at least twoof R₇, R₈, R₉, R₁₀, and R₁₁ are hydrogen.

In some variations, R₇, R₈, R₉, R₁₀, and R₁₁ are each independentlyselected from the group consisting of hydrogen, hydroxyl, (C₁₋₆)alkyl,halo(C₁₋₆)alkyl, —C(CH₃)(OH)CF₃, (C₁₋₈)alkoxy, halo, cyano,

where

k is 1, 2, 3, or 4; and

R₂₁ is selected from the group consisting of hydroxyl, (C₁₋₄)alkyl,halo(C₁₋₄)alkyl, alkyloxy, —(CH₂)_(n)OH, —CF₃, —(CH₂)_(n)CN,—(CH₂)_(n)COOH, —(CH₂)_(n)CONH₂, —(CH₂)_(n)heteroaryl, and—(CH₂)_(n)O(CH₂)_(n)heteroaryl, where n is 0, 1, 2, 3, or 4; or from thegroup consisting of methyl, perfluoromethyl, hydroxyl,hydroxyl(C₁₋₄)alkyl, and cyano(C₁₋₄)alkyl; or R₂₁ is hydroxyl; or R₂₁ ishydroxylmethyl; or R₂₁ is methyl; or R₂₁ is perfluoromethyl.

In some variations of the above embodiment, R₉ is selected from thegroup consisting of hydrogen, t-butyl, —C(CH₃)(OH)CF₃, —C(CH₂OH)(CH₃)₂;—C(OH)(CH₃)₂, and R₇, R₈, R₁₀, and R₁₁ are each hydrogen. In othervariations, R₉ is t-butyl. In still other variations, R₉ is—C(OH)(CH₃)₂. In yet still other variations, R₉ is —C(CH₃)(OH)CF₃. Inother further variations, R₉ is —C(CH₂OH)(CH₃)₂.

The compounds of the above two particularly special variations, in somevariations, ring B is selected from the group consisting of

In other variations, ring B is

In other variations, ring B is

In other variations, ring B is

Ring A

The compound according to any one of the above embodiments andvariations, in some variations, ring A is selected from the groupconsisting of (C₅₋₇)alicyclyl, hetero(C₁₋₆)alicyclyl,(C₈₋₁₁)bicycloalicyclyl, hetero(C₄₋₁₀)bicycloalicyclyl, (C₆)aryl,hetero(C₁₋₅)aryl, (C₈₋₁₀)bicycloaryl, and hetero(C₄₋₁₀)bicycloaryl, eachunsubstituted or substituted with said 1-5 substituents of ring A,

where

the hetero(C₁₋₆)alicyclyl, hetero(C₄₋₁₀)bicycloalicyclyl,hetero(C₁₋₅)aryl, and hetero(C₄₋₁₀)bicycloaryl each contains 1-4heteroatoms independently selected from the group consisting ofnitrogen, oxygen and sulfur; and

each (C₈₋₁₁)bicycloalicyclyl, hetero(C₄₋₁₀)bicycloalicyclyl,(C₈₋₁₀)bicycloaryl, and hetero(C₄₋₁₀)bicycloaryl consists of a firstring fused to a second ring, where the first ring attaches directly tothe ring containing N^(a), and where the second ring is selected from agroup consisting of five, six and seven membered cyclyls.

In some particular variations, ring A is selected from the groupconsisting of (C₆)aryl, hetero(C₂₋₅)aryl, (C₁₀)bicycloaryl, andhetero(C₅₋₁₀)bicycloaryl, each unsubstituted or substituted with said1-5 substituents of ring A,

wherein

the hetero(C₂₋₅)aryl is a six-membered heteroaryl;

the (C₉₋₁₀)bicycloaryl comprises a first ring that is a phenyl, and asecond ring that is a five membered heteroaryl or a phenyl;

the hetero(C₅₋₁₀)bicycloaryl comprises a first ring that is asix-membered heteroaryl, and a second ring that is selected from thegroup consisting of phenyl, five-membered heteraryl and six-memberedheteraryl;

each hetero(C₂₋₅)aryl and hetero(C₅₋₁₀)bicycloaryl contains 1-4heteroatoms each of which is independently selected from the groupconsisting of nitrogen, oxygen and sulfur.

In some variations of the above particular variations, ring A isselected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.

In other variations of the above particular variations, ring A isselected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.

In other particular variations, ring A is selected from the groupconsisting of hetero(C₁₋₄)aryl and hetero(C₄₋₉)bicycloaryl, eachunsubstituted or substituted with said 1-5 substituents of ring A,

where

the hetero(C₁₋₄)aryl is a five-membered heteroaryl,

the hetero(C₄₋₉)bicycloaryl comprises of a first ring that is afive-membered heteroaryl, and a second ring that is selected from thegroup of phenyl, and five, six and seven membered heteroaryl; and

each hetero(C₁₋₄)aryl and hetero(C₄₋₉)bicycloaryl contains 1-4heteroatoms each of which is independently selected from the groupconsisting of nitrogen, oxygen and sulfur.

In some variations of the above particular variations, ring A isselected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.In other variations, ring A is selected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.

In still other particular variations, ring A is selected from the groupconsisting of (C₆)alicyclyl, hetero(C₁₋₅)alicyclyl,(C₉₋₁₁)bicycloalicyclyl, and hetero(C₅₋₁₀)bicycloalicyclyl, eachunsubstituted or substituted with said 1-5 substituents of ring A,

wherein

the hetero(C₁₋₅)alicyclyl is a six-membered heteroalicyclyl;

the (C₉₋₁₁)bicycloalicyclyl comprises a first ring that is asix-membered alicyclyl, and a second ring that is selected from thegroup consisting of five, six and seven membered cyclyl;

the hetero(C₅₋₁₀)bicycloalicyclyl comprises a first ring that is asix-membered heteroalicyclyl, and a second ring that is a five, six orseven membered cyclyl;

each hetero(C₁₋₅)alicyclyl and hetero(C₅₋₁₀)bicycloalicyclyl contains1-4 heteroatoms, each of which is independently selected from the groupconsisting of nitrogen, oxygen and sulfur.

In some variations of the above particular variations, ring A isselected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.In other variations, ring A is selected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.In other variations, ring A is selected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.In other variations, ring A is selected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.

In yet still other particular variations, ring A is selected from thegroup consisting of (C₅)alicyclyl, hetero(C₁₋₄) alicyclyl,(C₈₋₁₀)bicycloalicyclyl, and hetero(C₄₋₉)bicycloalicyclyl, eachunsubstituted or substituted with said 1-5 substituents of ring A,

wherein

the hetero(C₁₋₄)alicyclyl is a five-membered heteroalicyclyl,

the (C₈₋₁₀)bicycloalicyclyl comprises a first ring that is afive-membered alicyclyl, and a second ring that is selected from thegroup consisting of five, six and seven membered cyclyl;

the hetero(C₄₋₉)bicycloalicyclyl comprises a first ring that is afive-membered heterocycloalicyclyl, and a second ring that is selectedfrom the group consisting of five, six and seven membered cyclyl; and

each hetero(C₁₋₄)alicyclyl and hetero(C₄₋₉)bicycloalicyclyl contains 1-4heteroatoms, each of which is independently selected from the groupconsisting of nitrogen, oxygen and sulfur.

In some variations of the above particular variations, ring A is of theformula

unsubstituted or substituted with said 1-5 substituents of ring A.

In still other particular variations, ring A is selected from the groupconsisting of (C₇)alicyclyl, hetero(C₃₋₆)alicyclyl,(C₁₀₋₁₁)bicycloalicyclyl, and hetero(C₆₋₁₀)bicycloalicyclyl, eachunsubstituted or substituted with said 1-5 substituents of ring A,

wherein

the hetero(C₃₋₆)alicyclyl is a seven-membered heterocycloalkyl;

the (C₁₀₋₁₁)bicycloalicyclyl comprises a first ring that is aseven-membered alicyclyl, and a second ring that is selected from thegroup consisting of five, six and seven membered cyclyl;

the hetero(C₆₋₁₀)bicycloalicyclyl comprises a first ring that is aseven-membered heteroalicyclyl and a second ring that is selected fromthe group consisting of five, six and seven membered cyclyl; and

each hetero(C₃₋₆)alicyclyl and hetero(C₆₋₁₀)bicycloalicyclyl contains1-4 heteroatoms, each of which is independently selected from the groupconsisting of nitrogen, oxygen and sulfur.

In some variation of the above particular variations, ring A is of theformula

unsubstituted or substituted with said 1-5 substituents of ring A.

In all the above embodiments and variations of the compounds of theinvention, the 1-5 substituents of ring A are each independentlyselected from the group consisting of halo, cyano, hydroxy, oxy, oxo,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, carbonylamino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl,(C₁₋₁₀)alkynyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)alicyclic, hetero(C₃₋₁₂)alicyclic, (C₄₋₁₂)aryl, andhetero(C₁₋₁₀)aryl, each unsubstituted or substituted.

In some variations, the 1-5 substituents of ring A is independentlyselected from the group consisting of hydroxyl, oxo, halo, cyano,(C₁₋₆)alkyl, (C₁₋₆)alkenyl, (C₁₋₆)alkynyl, halo(C₁₋₆)alkyl,(C₁₋₆)alkylcarbonylamino, (C₁₋₆)alkylaminocarbonyl, (C₁₋₆)alkoxy, amino,hydroxy(C₁₋₆)alkyl, (C₁₋₆)alkoxy(C₁₋₆)alkyl, (C₁₋₆)alkylcarbonyl,aminocarbonyl, hydroxylcarbonyl, and (C₁₋₆)alkylsulfonyl, eachunsubstituted or substituted.

In some other variations, the 1-5 substituents of ring A isindependently selected from the group consisting of hydroxyl, fluoro,chloro, cyano, oxo, methoxy, methyl, ethyl, hydroxymethyl,perfluoromethyl, methoxymethyl, methylcarbonylamino,methylaminocarbonylamino, aminocarbonyl, methylcarbonyl,hydroxycarbonyl, and methylsulfonyl.

The compound according to any one of the above embodiments andvariations, in some variations, ring A is selected from the groupconsisting of

In other variations, ring A is selected from the group consisting of

In other variations, ring A is selected from the group consisting of

In still other variations, ring A is selected from the group consistingof

In yet still other variations, ring A is of the formula

In yet still other variations, ring A is selected from the groupconsisting of

R₂

The compounds according to any one of the above embodiments andvariations, in some variations, R₂ is selected from the group consistingof hydrogen, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,(C₃₋₆)cycloalkyl(C₁₋₃)alkyl, hetero(C₁₋₅)cycloalkyl(C₁₋₃)alkyl,(C₃₋₆)cycloalkyl, and hetero(C₁₋₅)cycloalkyl, each substituted orunsubstituted.

In some other variations, R₂ is (C₁₋₆)alkyl.

In other variations, R₂ is (C₃₋₆)cycloalkyl.

In still other variations, R₂ is methyl.

In still other variations, R₂ is hydrogen.

R₃

The compounds according to any one of the above embodiments andvariations, in some variations, R₃, when present, is selected from thegroup consisting of hydrogen, hydroxyl, amino, thio, oxy, (C₁₋₆)alkyl,(C₁₋₆)cycloalkyl, and (C₁₋₆)alkoxy, each unsubstituted or substitutedwith 1-2 substituents each of which is independently selected from thegroup consisting of hydroxyl, halo, halo(C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, hetero(C₁₋₅)cycloalkyl, phenyl, and hetero(C₁₋₅)aryl.

In some other variations, R₃ when present is selected from the groupconsisting of hydrogen, methyl, ethyl, cyclopropyl, and methoxy.

In yet other variations, R₃ when present is selected is cyclopropyl.

In yet other variations, R₃ when present is selected is methyl.

In yet other variations, R₃ when present is selected is hydrogen.

In another embodiment, the compounds of the invention is of the formula

wherein

ring A is selected from the group consisting of (C₅₋₇)alicyclic,hetero(C₁₋₆)alicyclic, (C₈₋₁₁)bicycloalicyclic, andhetero(C₄₋₁₀)bicycloalicyclic, (C₆)aryl, hetero(C₁₋₅)aryl,(C₈₋₁₀)bicycloaryl, and hetero(C₄₋₁₀)bicycloaryl, each unsubstituted orsubstituted with 1-5 substituents that are each independently selectedfrom the group consisting of hydroxyl, oxo, halo, cyano, (C₁₋₆)alkyl,(C₁₋₆)alkenyl, (C₁₋₆)alkynyl, halo(C₁₋₆)alkyl, (C₁₋₆)alkylcarbonylamino,(C₁₋₆)alkylaminocarbonyl, (C₁₋₆)alkoxy, amino, hydroxy(C₁₋₆)alkyl,(C₁₋₆)alkoxy(C₁₋₆)alkyl, (C₁₋₆)alkylcarbonyl, aminocarbonyl,hydroxylcarbonyl, and (C₁₋₆)alkylsulfonyl, each unsubstituted orsubstituted;

R₃ is selected from the group consisting of hydrogen, methyl, ethyl,cyclopropyl, and methoxy; and

R₇, R₈, R₉, R₁₀, and R₁₁ are each independently selected from the groupconsisting of hydrogen, hydroxyl, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl,—C(CH₃)(OH)CF₃, (C₁₋₆)alkoxy, halo, cyano,

where

-   -   k is 1, 2, 3, or 4; and    -   R₂₁ is selected from the group consisting of hydroxyl,        (C₁₋₄)alkyl, halo(C₁₋₄)alkyl, alkyloxy, —(CH₂)_(n)OH, —CF₃,        —(CH₂)_(n)CN, —(CH₂)_(n)COOH, —(CH₂)_(n)CONH₂,        —(CH₂)_(n)heteroaryl, and —(CH₂)_(n)O(CH₂)_(n)heteroaryl, where        n is 0, 1, 2, 3, or 4.

In some variations of the above embodiment, R₃ is hydrogen.

In some variations of the above embodiment and variations, R₉ isindependently selected from the group consisting of hydrogen, t-butyl,—C(CH₃)(OH)CF₃, —C(OH)(CH₃)₂, and —C(CH₂OH)(CH₃)₂; and R₇, R₈, R₁₀, andR₁₁ are each hydrogen. In some other variations, R₉ is —C(OH)(CH₃)₂, andR₇, R₈, R₁₀and R₁₁ are each hydrogen. In still other variations, R₉ is—C(CH₂OH)(CH₃)₂; and R₇, R₈, R₁₀, and R₁₁ are each hydrogen.

In some variations of the above embodiment and variations, ring A isselected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.

In other variations, ring A is selected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.

In still other variations, ring A is selected from the group consistingof

each unsubstituted or substituted with said 1-5 substituents of ring A.

In some variations of each of the above embodiments and variations ofthe invention, ring A is selected from the group consisting of

In other variations, ring A is selected from the group consisting of

Particular examples of compounds according to the present inventioninclude, but are not limited to, the following:

N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-cyclopropylbenzamide;

N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide;

N-(5-(1H-imidazol-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-tert-butylbenzamide;

4-tert-butyl-N-(5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

N-(5-(1H-imidazol-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-tert-butylbenzamide;

N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;

N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide;

N-(5-(3,5-dimethyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-acetylbenzamide;

N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(1-methyl-1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

methyl4-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-ylcarbamoyl)benzoate;

4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

N-(5-(2-ethyl-1H-imidazol-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;

methyl 4-(5-(3-ethyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-carbamoyl)benzoate;

4-(2-hydroxypropan-2-yl)-N-(5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(3-methylpyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(4-(methylcarbamoyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(2-methoxypyrimidin-5-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

N-(5-(6-acetamidopyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

N-(5-(2-fluoropyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide;

N-(5-(6-aminopyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide;

4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(6-hydroxypyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(6-hydroxypyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

(R)-4-(2-hydroxypropan-2-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-morpholinothiazolo[5,4-b]pyridin-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(piperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(3-oxopiperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

N-(5-(2-chloropyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(2-methoxypyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(piperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

N-(5-(4-(hydroxymethyl)piperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;

N-(5-(6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(5-oxo-1,4-diazepan-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(4-methoxypiperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(4-methylpiperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

(S)-4-(2-hydroxypropan-2-yl)-N-(5-(2-(methoxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

N-(5-(4-acetylpiperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;

(R)-4-(2-hydroxypropan-2-yl)-N-(5-(2-(methoxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

N-(5-(3-cyanopiperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;

N-(5-(4-hydroxypiperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;

(S)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-2-carboxamide;

(R)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-2-carboxamide;

4-(2-hydroxypropan-2-yl)-N-(5-(4-oxo-3,4,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(5H)-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;

(S)-N-(5-(2-(hydroxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;

(S)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-3-carboxylicacid;

(R)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-3-carboxylicacid;

N-(5-(3-(hydroxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;

4-(2-hydroxypropan-2-yl)-N-(5-(4-(methylsulfonyl)piperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;and

4-(2-hydroxypropan-2-yl)-N-(5-(1,1-dioxothiomorpholino)thiazolo[5,4-b]pyridin-2-yl)benzamide.

It is noted that the compounds of the present invention may be in theform of a pharmaceutically acceptable salt, biohydrolyzable ester,biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate orprodrug thereof. For example, the compound optionally comprises asubstituent that is convertible in vivo to a different substituent suchas hydrogen.

It is further noted that the compound may be present as a mixture ofstereoisomers, or the compound may present as a single stereoisomer.

In another of its aspects, there is provided a pharmaceuticalcomposition comprising as an active ingredient a compound according toany one of the above embodiments and variations. In one particularvariation, the composition is a solid formulation adapted for oraladministration. In another particular variation, the composition is aliquid formulation adapted for oral administration. In yet anotherparticular variation, the composition is a tablet. In still anotherparticular variation, the composition is a liquid formulation adaptedfor parenteral administration.

The present invention also provides a pharmaceutical compositioncomprising a compound according to any one of the above embodiments andvariations, wherein the composition is adapted for administration by aroute selected from the group consisting of orally, parenterally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,liposomally, via inhalation, vaginally, intraoccularly, via localdelivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, and intrathecally.

In yet another of its aspects, there is provided a kit comprising acompound of any one of the above embodiments and variations; andinstructions which comprise one or more forms of information selectedfrom the group consisting of indicating a disease state for which thecomposition is to be administered, storage information for thecomposition, dosing information and instructions regarding how toadminister the composition. In one particular variation, the kitcomprises the compound in a multiple dose form.

In still another of its aspects, there is provided an article ofmanufacture comprising a compound of any one of the above embodimentsand variations; and packaging materials. In one variation, the packagingmaterial comprises a container for housing the compound. In oneparticular variation, the container comprises a label indicating one ormore members of the group consisting of a disease state for which thecompound is to be administered, storage information, dosing informationand/or instructions regarding how to administer the compound. In anothervariation, the article of manufacture comprises the compound in amultiple dose form.

In a further of its aspects, there is provided a therapeutic methodcomprising administering a compound of any one of the above embodimentsand variations to a subject.

In another of its aspects, there is provided a method of inhibiting ASK1comprising contacting ASK1 with a compound of any one of the aboveembodiments and variations.

In yet another of its aspects, there is provided a method of inhibitingASK1 comprising causing a compound of any one of the above embodimentsand variations to be present in a subject in order to inhibit ASK1 invivo.

In a further of its aspects, there is provided a method of inhibitingASK1 comprising administering a first compound to a subject that isconverted in vivo to a second compound wherein the second compoundinhibits ASK1 in vivo, the second compound being a compound according toany one of the above embodiments and variations.

In another of its aspects, there is provided a method of treating adisease state for which ASK1 possesses activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising causing a compound of any one of the above embodiments andvariations to be present in a subject in a therapeutically effectiveamount for the disease state.

In yet another of its aspects, there is provided a method of treating adisease state for which ASK1 possesses activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising administering a compound of any one of the above embodimentsand variations to a subject, wherein the compound is present in thesubject in a therapeutically effective amount for the disease state.

In a further of its aspects, there is provided a method of treating adisease state for which ASK1 possesses activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound inhibits ASK1in vivo, the second compound being a compound according to any one ofthe above embodiments and variations.

In some variations of each of the above treatment methods, the diseasestate is selected from the group consisting of metabolic diseases,inflammatory diseases, neurodegenerative diseases, autoimmune diseases,destructive bone disorders, infectious diseases, diseases and conditionsthat are mediated by inducible pro-inflammatory proteins,reperfusion/ischemia in stroke, cardiac hypertrophy, respiratorydiseases, heart attacks, myocardial ischemia, organ hypoxia, vascularhyperplasia, cardiac hypertrophy, hepatic ischemia, liver disease,congestive heart failure, pathologic immune responses, thrombin-inducedplatelet aggregation, gastroenterological diseases, hematologicaldiseases, and urological diseases.

In some other variations of each of the above treatment methods, thedisease state is selected from the group consisting of the disease stateis selected from the group consisting of diabetes, type 2 diabetesmellitus, diabetic dyslipidemia, impaired glucose tolerance (IGT),impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis,appetite regulation, obesity and complications associated with diabetesincluding diabetic neuropathy, diabetic retinopathy, inflammatory boweldisease, Crohn's disease, chemotherapy-induced enteritis, oralmucositis, Shortened Bowel Syndrome, kidney disease, hyperlipidemia,arteriosclerosis; hypertension; myocardial infarction, angina pectoris,cerebral infarction, cerebral apoplexy and metabolic syndrome.

In some other variations of each of the above treatment methods, thedisease state is selected from the group consisting of acutepancreatitis, chronic pancreatitis, asthma, allergies, chronicobstructive pulmonary disease, and adult respiratory distress syndrome.

In still some other variations of each of the above treatment methods,the disease state is selected from the group consisting of Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis (ALS),epilepsy, seizures, Huntington's disease, polyglutamine diseases,traumatic brain injury, ischemic and hemorrhaging stroke, cerebralischemias or neurodegenerative disease, including apoptosis-drivenneurodegenerative disease, caused by traumatic injury, acute hypoxia,ischemia or glutamate neurotoxicity.

In still other variations of each of the above treatment methods, thedisease state is selected from the group consisting ofglomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus,scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease,multiple sclerosis, or Sjoegren's syndrome.

In still other variations of each of the above treatment methods, thedisease state is selected from the group consisting of osteoporosis,osteoarthritis and multiple myeloma-related bone disorder.

In yet still other variations of each of the above treatment methods,the disease state is selected from the group consisting of sepsis,septic shock, and Shigellosis.

In yet still other variations of each of the above treatment methods,the disease state is selected from the group consisting of edema,analgesia, fever and pain, such as neuromuscular pain, headache, cancerpain, dental pain and arthritis pain.

In yet still other variations of each of the above treatment methods,the disease state is selected from the group consisting ofischemia/reperfusion in stroke, heart attacks, myocardial ischemia,organ hypoxia, vascular hyperplasia, cardiac hypertrophy, hepaticischemia, liver disease, congestive heart failure, pathologic immuneresponses such as that caused by T cell activation and thrombin-inducedplatelet aggregation.

Another aspect of the invention is directed to process for thepreparation of the inhibitor of the invention. In one embodiment, theprocess comprises coupling an intermediate compound of the formula

to a compound of the formula

under conditions that yield a product of the formula

wherein

ring A is selected from the group consisting of (C₅₋₇)alicyclyl,hetero(C₁₋₆)alicyclyl, (C₈₋₁₁)bicycloalicyclyl, andhetero(C₄₋₁₀)bicycloalicyclyl, (C₆)aryl, hetero(C₁₋₅)aryl,(C₈₋₁₀)bicycloaryl, and hetero(C₄₋₁₀)bicycloaryl, each unsubstituted orsubstituted with 1-5 substituents that are each independently selectedfrom the group consisting of hydroxyl, oxo, halo, cyano, (C₁₋₆)alkyl,(C₁₋₆)alkenyl, (C₁₋₆)alkynyl, halo(C₁₋₆)alkyl, (C₁₋₆)alkylcarbonylamino,(C₁₋₆)alkylaminocarbonyl, (C₁₋₆)alkoxy, amino, hydroxy(C₁₋₆)alkyl,(C₁₋₆)alkoxy(C₁₋₆)alkyl, (C₁₋₆)alkylcarbonyl, aminocarbonyl,hydroxylcarbonyl, and (C₁₋₆)alkylsulfonyl, each unsubstituted orsubstituted;

R₃ is selected from the group consisting of hydrogen, methyl, ethyl,cyclopropyl, and methoxy; and

R₇, R₈, R₉, R₁₀, and R₁₁ are each independently selected from the groupconsisting of hydrogen, hydroxyl, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl,—C(CH₃)(OH)CF₃, (C₁₋₆)alkoxy, halo, cyano,

where

-   -   k is 1, 2, 3, or 4; and    -   R₂₁ is selected from the group consisting of hydroxyl,        (C₁₋₄)alkyl, halo(C₁₋₄)alkyl, alkyloxy, —(CH₂)_(n)OH, —CF₃,        —(CH₂)_(n)CN, —(CH₂)_(n)COOH, —(CH₂)_(n)CONH₂,        —(CH₂)_(n)heteroaryl, and —(CH₂)_(n)O(CH₂)_(n)heteroaryl, where        n is 0, 1, 2, 3, or 4.

In some variations, the process further comprises coupling a compound ofthe formula

to a compound of the formula

under condition that yield the intermediate compound described above.

In some variations of the process of the invention, R₃ is hydrogen. Inother variations, R₃ is methyl.

In the above embodiment of the process of the invention, in somevariations, R₉ is —C(OH)(CH₃)₂, and R₇, R₈, R₁₀, and R₁₁ are eachhydrogen. In other variations, R₉ is —C(CH₂OH)(CH₃)₂; and R₇, R₈, R₁₀,and R₁₁ are each hydrogen.

In the above embodiment of the process of the invention, in somevariations, ring A is selected from the group consisting of

In other variations, ring A is selected from the group consisting of

Salts, Hydrates, and Prodrugs of ASK1 Inhibitors

It should be recognized that the compounds of the present invention maybe present and optionally administered in the form of salts, hydratesand prodrugs that are converted in vivo into the compounds of thepresent invention. For example, it is within the scope of the presentinvention to convert the compounds of the present invention into and usethem in the form of their pharmaceutically acceptable salts derived fromvarious organic and inorganic acids and bases in accordance withprocedures well known in the art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydroiodide; othermineral acids and their corresponding salts such as sulfate, nitrate,phosphate, etc.; and alkyl and monoarylsulfonates such asethanesulfonate, toluenesulfonate and benzenesulfonate; and otherorganic acids and their corresponding salts such as acetate, tartrate,maleate, succinate, citrate, benzoate, salicylate and ascorbate. Furtheracid addition salts of the present invention include, but are notlimited to: adipate, alginate, arginate, aspartate, bisulfate,bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate,chloride, chlorobenzoate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate,galacterate (from mucic acid), galacturonate, glucoheptonate, gluconate,glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate,lactobionate, malate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate and phthalate. It should be recognized that the free baseforms will typically differ from their respective salt forms somewhat inphysical properties such as solubility in polar solvents, but otherwisethe salts are equivalent to their respective free base forms for thepurposes of the present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base. Examples of such bases are alkalimetal hydroxides including potassium, sodium and lithium hydroxides;alkaline earth metal hydroxides such as barium and calcium hydroxides;alkali metal alkoxides, e.g., potassium ethanolate and sodiumpropanolate; and various organic bases such as ammonium hydroxide,piperidine, diethanolamine and N-methylglutamine. Also included are thealuminum salts of the compounds of the present invention. Further basesalts of the present invention include, but are not limited to: copper,ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,sodium and zinc salts. Organic base salts include, but are not limitedto, salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, e.g., arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, iso-propylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine andtris-(hydroxymethyl)-methylamine(tromethamine). It should be recognizedthat the free acid forms will typically differ from their respectivesalt forms somewhat in physical properties such as solubility in polarsolvents, but otherwise the salts are equivalent to their respectivefree acid forms for the purposes of the present invention.

Compounds of the present invention that comprise basic nitrogencontaining groups may be quaternized with such agents as (C₁₋₄) alkylhalides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides,bromides and iodides; di (C₁₋₄) alkyl sulfates, e.g., dimethyl, diethyland diamyl sulfates; (C₁₀₋₁₈) alkyl halides, e.g., decyl, dodecyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl(C₁₋₄) alkyl halides, e.g., benzyl chloride and phenethyl bromide. Suchsalts permit the preparation of both water-soluble and oil-solublecompounds of the present invention.

N-oxides of compounds according to the present invention can be preparedby methods known to those of ordinary skill in the art. For example,N-oxides can be prepared by treating an unoxidized form of the compoundwith an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid,perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or thelike) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethane) at approximately 0° C.Alternatively, the N-oxides of the compounds can be prepared from theN-oxide of an appropriate starting material.

Prodrug derivatives of compounds according to the present invention canbe prepared by modifying substituents of compounds of the presentinvention that are then converted in vivo to a different substituent. Itis noted that in many instances, the prodrugs themselves also fallwithin the scope of the range of compounds according to the presentinvention. For example, prodrugs can be prepared by reacting a compoundwith a carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like) or an acylating agent. Furtherexamples of methods of making prodrugs are described in Saulnier et al.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.

Protected derivatives of compounds of the present invention can also bemade. Examples of techniques applicable to the creation of protectinggroups and their removal can be found in P. G. M. Wuts and T. W. Greenein “Greene's Protective Groups in Organic Synthesis” 4th edition, JohnWiley and Sons, 2007.

Compounds of the present invention may also be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

A “pharmaceutically acceptable salt”, as used herein, is intended toencompass any compound according to the present invention that isutilized in the form of a salt thereof, especially where the saltconfers on the compound improved pharmacokinetic properties as comparedto the free form of compound or a different salt form of the compound.The pharmaceutically acceptable salt form may also initially conferdesirable pharmacokinetic properties on the compound that it did notpreviously possess, and may even positively affect the pharmacodynamicsof the compound with respect to its therapeutic activity in the body. Anexample of a pharmacokinetic property that may be favorably affected isthe manner in which the compound is transported across cell membranes,which in turn may directly and positively affect the absorption,distribution, biotransformation and excretion of the compound. While theroute of administration of the pharmaceutical composition is important,and various anatomical, physiological and pathological factors cancritically affect bioavailability, the solubility of the compound isusually dependent upon the character of the particular salt formthereof, which it utilized. One of skill in the art will appreciate thatan aqueous solution of the compound will provide the most rapidabsorption of the compound into the body of a subject being treated,while lipid solutions and suspensions, as well as solid dosage forms,will result in less rapid absorption of the compound.

Uses for the Compounds of the Invention

ASK1 activates the p38 and JNK pro-apoptotic pathways in response toenvironmental stresses. Wang et al. J. Biol. Chem. 1996, 271,31607-31611; Ichijo et al. Science 1997, 275, 90-94. ASK1 inducesapoptosis through ASK1-p38/JNK cascades in response to pro-apoptoticstresses (e.g. oxidative stress and TNF) and pathogenic stresses (e.g.ER stress, GPCR-and Aβ-induced ROS production). Overexpression ofwild-type or constitutively active ASK1 induces apoptosis in variouscells through mitochondria-dependent caspase activation. Saitoh et alEMBO J. 1998, 17:2596-2606; Kanamoto et al. Mol. Cell Biol. 2000, 20,196-204; Hatai et al. J. Biol. Chem. 2000, 275, 26576-2658.

Apoptosis plays an essential role in normal development and tissuehomeostasis; such that when dysregulated, it contributes to multiplediseases including, but are not limited to, amyloidosis,hypercholesterolemia, diabetes mellitus, cancers, inflammatory diseases,autoimmune diseases, destructive bone disorders, infectious diseases,neurodegenerative diseases, reperfusion/ischemia in stroke, cardiachypertrophy respiratory diseases, metabolic diseases,gastroenterological diseases, hematological diseases, and urologicaldiseases. Thompson, Science 1995, 267, 1456-1462; Yuan and Yanker Nature2000, 407, 802-809; Los et al. Immunity 1999, 10, 629-639; Aridor andBalch, Nat. Med. 1999, 5, 745-751; Kopito and Ron, Nat. Cell Biol. 2000,2, E207-E209; Nakagawa et al. Nature 2000, 403, 98-103; Imai et al. Cell2001, 105, 891-902; Harding et al. Mol Cell 2001, 7, 1153-1163; andNishitoh et al. Genes Dev. 2002, 16, 1345-1355.

Recent studies revealed that ASK1 contributes not only to regulation ofcell death but also has diverse functions in the decision of cell fatesuch as cytokine responses, cell differentiation, and innate immuneresponses. Matsukawa et al. J. Biochem. (Toyko) 2004, 136, 261-265.Sayama et al. J. Biol. Chem. 2000, 276:999-1004; Takeda et al. J. Biol.Chem. 2000, 275:9805-9813; Sagasti et al. Cell 2001, 105:221-232; Kim atal. Science 2002, 297:623-626; Nishitoh et al. Genes Dev. 2002,16:1345-1355; Matsukawa et al. Nat Immunol 2005, 6, 587-592; Tobiume etal. EMBO Rep. 2001, 2:222-228; Imoto, et al. Diabetes 2006,55:1197-1204. Constitutively active ASK1 induces neurite outgrowth inPC12 cells. ASK1 is activated by CaMKII, which activates ASK1-p38pathway in neurons, suggesting that ASK1 might play critical roles insynaptic plasticity. Moreover, TRAF6-ASK1-p38 pathway plays an essentialrole in inflammatory and innate immune responses. Hayakaw et al.Microbes and Infection 2006, 8, 1098-1107. It has also been demonstratedthat ASK1 has a role in the pathogenesis of TNF-α-induced insulinresistance. Overexpression of wild-type ASK1 increases serinephosphorylation of insulin receptor substrate (IRS)-1, and decreasesinsulin-stimulated tyrosine phosphorylation of IRS-1, leading to impairinsulin signaling. Imoto, et al. Diabetes 2006, 55:1197-1204.

Accordingly, modulating the activity of ASK1 by the compounds of theinvention would have impact of a multiple of diseases and condition; inparticularly, metabolic diseases, inflammatory diseases,neurodegenerative diseases, autoimmune diseases, destructive bonedisorders, infectious diseases, diseases and conditions that aremediated by inducible pro-inflammatory proteins, reperfusion/ischemia instroke, cardiac hypertrophy, respiratory diseases, heart attacks,myocardial ischemia, organ hypoxia, vascular hyperplasia, cardiachypertrophy, hepatic ischemia, liver disease, congestive heart failure,pathologic immune responses, thrombin-induced platelet aggregation,gastroenterological diseases, hematological diseases, and urologicaldiseases.

Metabolic diseases which may be treated or prevented by the compounds ofthis invention include, but are not limited to, diabetes, particularly,type 2 diabetes mellitus, diabetic dislipidemia, impaired glucosetolerance (IGT), impaired fasting plasma glucose (IFG), metabolicacidosis, ketosis, appetite regulation, obesity and complicationsassociated with diabetes including diabetic neuropathy, diabeticretinopathy, inflammatory bowel disease, Crohn's disease,chemotherapy-induced enteritis, oral mucositis, Shortened Bowel Syndromeand kidney disease. The conditions mediated by ASK1 inhibitors of theinvention further include hyperlipidemia such as hypertriglyceridemia,hypercholesteremia, hypoHDLemia and postprandial hyperlipidemia;arteriosclerosis; hypertension; myocardial infarction, angina pectoris,cerebral infarction, cerebral apoplexy and metabolic syndrome.

Inflammatory diseases which may be treated or prevented by the compoundsof this invention include, but are not limited to, acute pancreatitis,chronic pancreatitis, asthma, allergies, chronic obstructive pulmonarydisease, adult respiratory distress syndrome.

Neurodegenerative diseases which may be treated or prevented by thecompounds of this invention include, but are not limited to, Alzheimer'sdisease (Nakagawa et al. Nature 2000, 403, 98-103), Parkinson's disease(Imai et al. Cell 2001, 105, 891-902), amyotrophic lateral sclerosis(ALS), epilepsy, seizures, Huntington's disease, polyglutamine diseases(Nishitoh et al. Genes Dev. 2002, 16, 1345-1355), traumatic braininjury, ischemic and hemorrhaging stroke, cerebral ischemias orneurodegenerative disease, including apoptosis-driven neurodegenerativedisease, caused by traumatic injury, acute hypoxia, ischemia orglutamate neurotoxicity.

Autoimmune diseases which may be treated or prevented by the compoundsof this invention include, but are not limited to, glomerulonephritis,rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronicthyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmunehemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopicdermatitis, chronic active hepatitis, myasthenia gravis, multiplesclerosis, inflammatory bowel disease, ulcerative colitis, Crohn'sdisease, psoriasis, graft vs. host disease, multiple sclerosis, orSjoegren's syndrome.

Destructive bone disorders which may be treated or prevented by thecompounds of this invention include, but are not limited to,osteoporosis, osteoarthritis and multiple myeloma-related bone disorder.

Infectious diseases which may be treated or prevented by the compoundsof this invention include, but are not limited to, sepsis, septic shock,and Shigellosis.

Diseases and conditions that are mediated by inducible pro-inflammatoryproteins which may be treated or prevented by the compounds of thisinvention include, but are not limited to, edema, analgesia, fever andpain, such as neuromuscular pain, headache, cancer pain, dental pain andarthritis pain.

Other conditions that are mediated by ASK1 and may be treated orprevented by the compounds of this invention include, but are notlimited to, ischemia/reperfusion in stroke, heart attacks, myocardialischemia, organ hypoxia, vascular hyperplasia, cardiac hypertrophy,hepatic ischemia, liver disease, congestive heart failure, pathologicimmune responses such as that caused by T cell activation, andthrombin-induced platelet aggregation.

Combination Therapy

A wide variety of therapeutic agents may have a therapeutic additive orsynergistic effect with ASK1 inhibitors according to the presentinvention. Combination therapies that comprise one or more compounds ofthe present invention with one or more other therapeutic agents can beused, for example, to: 1) enhance the therapeutic effect(s) of the oneor more compounds of the present invention and/or the one or more othertherapeutic agents; 2) reduce the side effects exhibited by the one ormore compounds of the present invention and/or the one or more othertherapeutic agents; and/or 3) reduce the effective dose of the one ormore compounds of the present invention and/or the one or more othertherapeutic agents. It is noted that combination therapy is intended tocover when agents are administered before or after each other(sequential therapy) as well as when the agents are administered at thesame time.

The present invention particularly relates to the use of the compoundsof the invention in combination with one or more other antidiabeticagents. Examples of such other antidiabetic agents include, but are notlimited to insulin signaling pathway modulators, like protein tyrosinephosphatase (PTPase) inhibitors, and glutamine-fructose-6-phosphateamidotransferase (GFAT) inhibitors; compounds influencing a dysregulatedhepatic glucose production, like glucose-6-phosphatase (G6Pase)inhibitors, fructose-1,6-bisphosphatase (F-1,6-BPase) inhibitors,glycogen phosphorylase (GP) inhibitors, glucagon receptor antagonistsand phosphoenolpyruvate carboxykinase (PEPCK) inhibitors; pyruvatedehydrogenase kinase (PDHK) inhibitors; insulin sensitivity enhancers(insulin sensitizers); insulin secretion enhancers (insulinsecretagogues); alpha-glucosidase inhibitors; inhibitors of gastricemptying; glucokinase activators, GLP-1 receptor agonists, GLP-2receptor agonists, UCP modulators, RXR modulators, GSK-3 inhibitors,PPAR modulators, metformin, insulin; and U2-adrenergic antagonists. ASK1inhibitors may be administered with such at least one other antidiabeticcompound either simultaneously as a single dose, at the same time asseparate doses, or sequentially (i.e., where one is administered beforeor after the other is administered).

Examples of PTPase inhibitors that may be used in combination with ASK1inhibitors of the invention include, but are not limited to thosedisclosed in U.S. Pat. Nos. 6,057,316, 6,001,867, and PCT PublicationNos. WO 99/58518, WO 99/58522, WO 99/46268, WO 99/46267, WO 99/46244, WO99/46237, WO 99/46236, and WO 99/15529.

Examples of GFAT inhibitors that may be used in combination with ASK1inhibitors of the invention include, but are not limited to thosedisclosed in Mol. Cell. Endocrinol. 1997, 135(1), 67-77.

Examples of G6Pase inhibitors that may be used in combination with ASK1inhibitors of the invention include, but are not limited to thosedisclosed in PCT Publication Nos. WO 00/14090, WO 99/40062 and WO98/40385, European Patent Publication No. EP682024 and Diabetes 1998,47,1630-1636.

Examples of F-1,6-BPase inhibitors that may be used in combination withASK1 inhibitors of the invention include, but are not limited to thosedisclosed in PCT Publication Nos. WO 00/14095, WO 99/47549, WO 98/39344,WO 98/39343 and WO 98/39342.

Examples of GP inhibitors that may be used in combination with ASK1inhibitors of the invention include, but are not limited to thosedisclosed in U.S. Pat. No. 5,998,463, PCT Publication Nos. WO 99/26659,WO 97/31901, WO 96/39384 and WO9639385 and European Patent PublicationNos. EP 978279 and EP 846464.

Examples of glucagon receptor antagonists that may be used incombination with ASK1 inhibitors of the invention include, but are notlimited to those disclosed in U.S. Pat. Nos. 5,880,139 and 5,776,954,PCT Publication Nos. WO 99/01423, WO 98/22109, WO 98/22108, WO 98/21957,WO 97/16442 and WO 98/04528 and those described in Bioorg Med. Chem.Lett 1992, 2, 915-918, J. Med. Chem. 1998, 41, 5150-5157, and J. BiolChem. 1999, 274, 8694-8697.

Examples of PEPCK inhibitors that may be used in combination with ASK1inhibitors of the invention include, but are not limited to thosedisclosed in U.S. Pat. No. 6,030,837 and Mol. Biol. Diabetes 1994, 2,283-99.

Examples of PDHK inhibitors that may be used in combination with ASK1inhibitors of the invention include, but are not limited to thosedisclosed in J. Med. Chem. 1999, 42, 2741-2746.

Examples of insulin sensitivity enhancers that may be used incombination with ASK1 inhibitors of the invention include, but are notlimited to GSK-3 inhibitors, retinoid X receptor (RXR) agonists, Beta-3AR agonists, UCP modulators, antidiabetic thiazolidinediones(glitazones), non-glitazone type PPAR gamma agonists, dual PPARgamma/PPAR alpha agonists, antidiabetic vanadium containing compoundsand biguanides such as metformin.

Examples of GSK-3 inhibitors include, but are not limited to thosedisclosed in PCT Publication Nos. WO 00/21927 and WO 97/41854.

Examples of RXR modulators include, but are not limited to thosedisclosed in U.S. Pat. Nos. 4,981,784, 5,071,773, 5,298,429 and5,506,102 and PCT Publication Nos. WO89/05355, WO91/06677, WO92/05447,WO93/11235, WO95/18380, WO94/23068, and WO93/23431.

Examples of Beta-3 AR agonists include, but are not limited toCL-316,243 (Lederle Laboratories) and those disclosed in U.S. Pat. No.5,705,515 and PCT Publication Nos. WO 99/29672, WO 98/32753, WO98/20005, WO 98/09625, WO 97/46556, and WO 97/37646.

Examples of UCP modulators include agonists of UCP-1, UCP-2 and UCP-3.Examples of UCP modulators include, but are not limited to thosedisclosed in Vidal-Puig et al., Biochem. Biophys. Res. Commun., 1997,235(1), 79-82.

Examples of antidiabetic, PPAR modulating thiazolidinediones(glitazones) include, but are not limited to,(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione(englitazone),5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thiazolidine-2,4-dione(darglitazone),5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl]-thiazolidine-2,4-dione(ciglitazone),5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione(DRF2189),5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-dione(BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637),bis{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane (YM268),5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolidine-2,4-dione(AD-5075),5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione(DN-108)5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-dione,5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione,5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione,5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione(rosiglitazone),5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione(pioglitazone; marketed under the trademark ACTOS™),5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2,4-dione(MCC555),5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione(T-174), edaglitazone (BM-13-1258), rivoglitazone (CS-011), and5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide(KRP297).

Examples of non-glitazone type PPAR gamma agonists include, but are notlimited to N-(2-benzoylphenyl)-L-tyrosine analogues, such as GI-262570,reglixane (JTT501), and FK-614 and metaglidasen (MBX-102).

Examples of dual PPAR gamma/PPAR alpha agonists include, but are notlimited to omega.-[(oxoquinazolinylalkoxy)phenyl]alkanoates and analogsthereof including those described in PCT Publication No. WO 99/08501 andDiabetes 2000, 49(5), 759-767; tesaglitazar, muraglitazar andnaveglitazar.

Examples of antidiabetic vanadium containing compounds include, but arenot limited to those disclosed in the U.S. Pat. No. 5,866,563.

Metformin (dimethyldiguanide) and its hydrochloride salt is marketedunder the trademark GLUCOPHAGE™.

Examples of insulin secretion enhancers include but are not limited toglucagon receptor antagonists (as described above), sulphonyl ureaderivatives, incretin hormones or mimics thereof, especiallyglucagon-like peptide-1 (GLP-1) or GLP-1 agonists, beta-cell imidazolinereceptor antagonists, and short-acting insulin secretagogues, likeantidiabetic phenylacetic acid derivatives, antidiabetic D-phenylalaninederivatives, and mitiglinide and pharmaceutical acceptable saltsthereof.

Examples of sulphonyl urea derivatives include, but are not limited to,glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide,glibornuride, tolbutamide, tolazamide, glipizide, carbutamide,gliquidone, glyhexamide, phenbutamide, tolcyclamide; glimepiride andgliclazide. Tolbutamide, glibenclamide, gliclazide, glibornuride,gliquidone, glisoxepid and glimepiride can be administered in the formthat they are marketed under the trademarks RASTINON HOECHST™,AZUGLUCON™, DIAMICRONT™, GLUBORID™, GLURENORM™, PRO-DIABAN™ and AMARYL™,respectively.

Examples of GLP-1 agonists include, but are not limited to thosedisclosed in U.S. Pat. Nos. 5,120,712, 5,118,666 and 5,512,549, and PCTPublication No. WO 91/11457. In particular, GLP-1 agonists include thosecompounds like GLP-1 (7-37) in which compound the carboxy-terminal amidefunctionality of Arg³⁶ is displaced with Gly at the 37^(th) position ofthe GLP-1 (7-36)NH₂ molecule and variants and analogs thereof includingGLN⁹-GLP-1 (7-37), D-GLN⁹-GLP-1 (7-37), acetyl LYS⁹-GLP-1 (7-37),LYS¹⁸-GLP-1 (7-37) and, in particular, GLP-1 (7-37)OH, VAL⁸-GLP-1(7-37), GLY⁸-GLP-1(7-37), THR⁸-GLP-1 (7-37), GLP-1 (7-37) and4-imidazopropionyl-GLP-1.

One particular example of a GLP-1 agonist is Exendatide, a 39-amino acidpeptide amide, which is marketed under the trademark BYETTA™.Extendatide has the empirical formula C₁₈₄H₂₈₂N₅₀O₆₀S and molecularweight of 4186.6 Daltons. The amino acid sequence for Extendatide is asfollows:H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH₂.

Examples of glucagon-like peptide-2 (GLP-2) or GLP-2 agonists include,but are not limited to those disclosed in U.S. Pat. No. 7,056,886 andPCT Publication Nos. WO 00/53208, WO 01/49314 and WO 03/099854. Oneparticular example of a GLP-2 agonist is TEDUGLUTIDE™, a 39-amino acidpeptide amide (NPS Pharmaceuticals, Inc.).

Examples of beta-cell imidazoline receptor antagonists include, but arenot limited to those described in PCT Publication No. WO 00/78726 and J.Pharmacol. Exp. Ther. 1996, 278, 82-89.

An example of an antidiabetic phenylacetic acid derivative isrepaglinide and pharmaceutically acceptable salts thereof.

Examples of antidiabetic D-phenylalanine derivatives include, but arenot limited to nateglinide(N-[(trans4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine, EP 196222and EP 526171) and repaglinide((S)-2-ethoxy-4-{2-[[3-methy-1-1-[2-(1-piperidinyl)phenyl]buytl]-amino]-2-oxoethyl}benzoicacid, EP 0 147 850 A2 and EP 0 207 331 A1). Nateglinide is intended toinclude the particular crystal forms (polymorphs) disclosed in U.S. Pat.No. 5,488,510 and European Patent Publication No. EP 0526171 B1.Repaglinide and nateglinide may be administered in the form as they aremarketed under the trademarks NOVONORMTM and STARLIX™, respectively.

Examples of alpha-Glucosidase inhibitors include, but are not limitedto, acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine (voglibose) and the1-deoxynojirimycin derivative miglitol. Acarbose is4″,6″-dideoxy-4′-[(1S)-(1,4,6/5)-4,5,6-trihydroxy-3-hydroxymethyl-2-cyclo-hexenylamino)maltotriose.The structure of acarbose can as well be described asO-4,6-dideoxy-4-{[1S,4R,5S,6S]-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]-amino)-alpha-D-glucopyranosyl-(1-4)-O-alpha-D-glucopyranosyl-(1-4)-D-glucopyranose. (U.S. Pat. No. 4,062,950and European Patent Publication No. EP 0 226 121). Acarbose and miglitolmay be administered in the forms that they are marketed under thetrademarks GLUCOBAY™ and DIASTABOL 50™ respectively.

Examples of inhibitors of gastric emptying other than GLP-1 include, butare not limited to those disclosed in J. Clin. Endocrinol. Metab. 2000,85(3), 1043-1048, and Diabetes Care 1998, 21, 897-893, especially Amylinand analogs thereof such as pramlintide. Amylin is described inDiabetologia, 1996, 39, 492-499.

Examples of α₂-adrenergic antagonists include, but are not limited tomidaglizole which is described in Diabetes 1987, 36, 216-220. Theinsulin that may be used in combination with ASK1 inhibitors of theinvention include, but are not limited to animal insulin preparationsextracted from the pancreas of bovine and pig; human insulinpreparations genetically synthesized using Escherichia coli or yeast;zinc insulin; protamine zinc insulin; fragment or derivative of insulin(e.g., INS-1) and an oral insulin preparation.

In one particular embodiment, the antidiabetic compound administered incombination with ASK1 inhibitors of the invention is selected from thegroup consisting of nateglinide, mitiglinide, repaglinide, metformin,extendatide, rosiglitazone, tesaglitazar, pioglitazone, glisoxepid,glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride,tolbutamide, tolazamide, glipizide, carbutamide, gliquidone,glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide,including any pharmaceutically acceptable salts thereof.

Examples of the preparation and formulation of PTPase inhibitors, GSK-3inhibitors, non-small molecule mimetic compounds, GFAT inhibitors,G6Pase inhibitors, glucagon receptor antagonists, PEPCK inhibitors,F-1,6-BPase inhibitors, GP inhibitors, RXR modulators, Beta-3 ARagonists, PDHK inhibitors, inhibitors of gastric emptying and UCPmodulators are disclosed in the patents, applications and referencesprovided herein.

In the case of combination therapy with Compound I, the otherantidiabetic compound may be administered (e.g., route and dosage form)in a manner known per se for such compound. ASK1 inhibitors of theinvention and the other antidiabetic compound may be administeredsequentially (i.e., at separate times) or at the same time, either oneafter the other separately in two separate dose forms or in onecombined, single dose form. In one particular embodiment, the otherantidiabetic compound is administered with ASK1 inhibitors of theinvention as a single, combined dosage form. The dose of theantidiabetic compound may be selected from the range known to beclinically employed for such compound. Any therapeutic compounds ofdiabetic complications, antihyperlipemic compounds, antiobesticcompounds or antihypertensive compounds can be used in combination withASK1 inhibitors of the invention in the same manner as the aboveantidiabetic compounds. Examples of therapeutic compounds of diabeticcomplications include, but are not limited to, aldose reductaseinhibitors such as tolrestat, epalrestat, zenarestat, zopolrestat,minalrestat, fidarestat, CT-112 and ranirestat; neurotrophic factors andincreasing compounds thereof such as NGF, NT-3, BDNF and neurotrophinproduction-secretion promoters described in WO01/14372 (e.g.,4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole);neuranagenesis stimulators such as Y-128; PKC inhibitors such asruboxistaurin mesylate; AGE inhibitors such as ALT946, pimagedine,N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226, pyridorin andpyridoxamine; reactive oxygen scavengers such as thioctic acid; cerebralvasodilators such as tiapride and mexiletine; somatostatin receptoragonists such as BIM23190; and apoptosis signal regulating kinase-1(ASK-1) inhibitors. Examples of antihyperlipemic compounds include, butare not limited to, HMG-CoA reductase inhibitors such as pravastatin,simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin andpitavastatin; squalene synthase inhibitors such as compounds describedin WO97/10224 (e.g.,N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]-piperidine-4-aceticacid); fibrate compounds such as bezafibrate, clofibrate, simfibrate andclinofibrate; ACAT inhibitors such as avasimibe and eflucimibe; anionexchange resins such as colestyramine; probucol; nicotinic acid drugssuch as nicomol and niceritrol; ethyl icosapentate; and plant sterolssuch as soysterol and γ-oryzanol. Examples of antiobestic compoundsinclude, but are not limited to, dexfenfluramine, fenfluramine,phentermine, sibutramine, amfepramone, dexamphetamine, mazindol,phenylpropanolamine, clobenzorex; MCH receptor antagonists such asSB-568849 and SNAP-7941; neuropeptide Y antagonists such as CP-422935;cannabinoid receptor antagonists such as SR-141716 and SR-147778;ghrelin antagonist; 11β-hydroxysteroid dehydrogenase inhibitors such asBVT-3498; pancreatic lipase inhibitors such as orlistat and ATL-962;Beta-3 AR agonists such as AJ-9677; peptidic anorexiants such as leptinand CNTF (Ciliary Neurotropic Factor); cholecystokinin agonists such aslintitript and FPL-15849; and feeding deterrent such as P-57. Examplesof the antihypertensive compounds include angiotensin converting enzymeinhibitors such as captopril, enalapril and delapril; angiotensin IIantagonists such as candesartan cilexetil, losartan, eprosartan,valsartan, telmisartan, irbesartan, olmesartan medoxomil, tasosartan and1-[[2′-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylicacid; calcium channel blockers such as manidipine, nifedipine,nicardipine, amlodipine and efonidipine; potassium channel openers suchas levcromakalim, L-27152, AL0671 and NIP-121; and clonidine.

The structure of the active agents identified herein by code nos.,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications). The corresponding contentthereof is hereby incorporated by reference. Any person skilled in theart is fully enabled to identify the active agents and, based on thesereferences, likewise enabled to manufacture and test the pharmaceuticalindications and properties in standard test models, both in vitro and invivo.

Compositions Comprising ASK1 Inhibitors

A wide variety of compositions and administration methods may be used inconjunction with the compounds of the present invention. Suchcompositions may include, in addition to the compounds of the presentinvention, conventional pharmaceutical excipients, and otherconventional, pharmaceutically inactive agents. Additionally, thecompositions may include active agents in addition to the compounds ofthe present invention. These additional active agents may includeadditional compounds according to the invention, and/or one or moreother pharmaceutically active agents.

The compositions may be in gaseous, liquid, semi-liquid or solid form,formulated in a manner suitable for the route of administration to beused. For oral administration, capsules and tablets are typically used.For parenteral administration, reconstitution of a lyophilized powder,prepared as described herein, is typically used.

Compositions comprising compounds of the present invention may beadministered or coadministered orally, parenterally, intraperitoneally,intravenously, intraarterially, transdermally, sublingually,intramuscularly, rectally, transbuccally, intranasally, liposomally, viainhalation, vaginally, intraoccularly, via local delivery (for exampleby catheter or stent), subcutaneously, intraadiposally,intraarticularly, or intrathecally. The compounds and/or compositionsaccording to the invention may also be administered or coadministered inslow release dosage forms.

The ASK1 inhibitors and compositions comprising them may be administeredor coadministered in any conventional dosage form. Co-administration inthe context of this invention is intended to mean the administration ofmore than one therapeutic agent, one of which includes an ASK1inhibitor, in the course of a coordinated treatment to achieve animproved clinical outcome. Such co-administration may also becoextensive, that is, occurring during overlapping periods of time.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application may optionally include one or more of thefollowing components: a sterile diluent, such as water for injection,saline solution, fixed oil, polyethylene glycol, glycerine, propyleneglycol or other synthetic solvent; antimicrobial agents, such as benzylalcohol and methyl parabens; antioxidants, such as ascorbic acid andsodium bisulfite; chelating agents, such as ethylenediaminetetraaceticacid (EDTA); buffers, such as acetates, citrates and phosphates; agentsfor the adjustment of tonicity such as sodium chloride or dextrose, andagents for adjusting the acidity or alkalinity of the composition, suchas alkaline or acidifying agents or buffers like carbonates,bicarbonates, phosphates, hydrochloric acid, and organic acids likeacetic and citric acid. Parenteral preparations may optionally beenclosed in ampules, disposable syringes or single or multiple dosevials made of glass, plastic or other suitable material.

When compounds according to the present invention exhibit insufficientsolubility, methods for solubilizing the compounds may be used. Suchmethods are known to those of skill in this art, and include, but arenot limited to, using cosolvents, such as dimethylsulfoxide (DMSO),using surfactants, such as TWEEN, or dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as prodrugs of thecompounds may also be used in formulating effective pharmaceuticalcompositions.

Upon mixing or adding compounds according to the present invention to acomposition, a solution, suspension, emulsion or the like may be formed.The form of the resulting composition will depend upon a number offactors, including the intended mode of administration, and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration needed to ameliorate the disease being treatedmay be empirically determined.

Compositions according to the present invention are optionally providedfor administration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, dry powders for inhalers, granules,sterile parenteral solutions or suspensions, and oral solutions orsuspensions, and oil-water emulsions containing suitable quantities ofthe compounds, particularly the pharmaceutically acceptable salts,preferably the sodium salts, thereof. The pharmaceuticallytherapeutically active compounds and derivatives thereof are typicallyformulated and administered in unit-dosage forms or multiple-dosageforms. Unit-dose forms, as used herein, refers to physically discreteunits suitable for human and animal subjects and packaged individuallyas is known in the art. Each unit-dose contains a predetermined quantityof the therapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes individually packaged tablet or capsule. Unit-doseforms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pint or gallons. Hence, multipledose form is a multiple of unit-doses that are not segregated inpackaging.

In addition to one or more compounds according to the present invention,the composition may comprise: a diluent such as lactose, sucrose,dicalcium phosphate, or carboxymethylcellulose; a lubricant, such asmagnesium stearate, calcium stearate and talc; and a binder such asstarch, natural gums, such as gum acaciagelatin, glucose, molasses,polyvinylpyrrolidine, celluloses and derivatives thereof, povidone,crospovidones and other such binders known to those of skill in the art.Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, or otherwise mixing an activecompound as defined above and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, glycols, ethanol, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of auxiliary substances suchas wetting agents, emulsifying agents, or solubilizing agents, pHbuffering agents and the like, for example, acetate, sodium citrate,cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodiumacetate, triethanolamine oleate, and other such agents. Actual methodsof preparing such dosage forms are known in the art, or will beapparent, to those skilled in this art; for example, see Remington: TheScience and Practices of Pharmacy, Lippincott Williams, and WilkinsPublisher, 21^(st) edition, 2005. The composition or formulation to beadministered will, in any event, contain a sufficient quantity of aninhibitor of the present invention to reduce ASK1 activity in vivo,thereby treating the disease state of the subject.

Dosage forms or compositions may optionally comprise one or morecompounds according to the present invention in the range of 0.005% to100% (weight/weight) with the balance comprising additional substancessuch as those described herein. For oral administration, apharmaceutically acceptable composition may optionally comprise any oneor more commonly employed excipients, such as, for examplepharmaceutical grades of mannitol, lactose, starch, magnesium stearate,talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose,magnesium carbonate, sodium saccharin, talcum. Such compositions includesolutions, suspensions, tablets, capsules, powders, dry powders forinhalers and sustained release formulations, such as, but not limitedto, implants and microencapsulated delivery systems, and biodegradable,biocompatible polymers, such as collagen, ethylene vinyl acetate,polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid andothers. Methods for preparing these formulations are known to thoseskilled in the art. The compositions may optionally contain 0.01%-100%(weight/weight) of one or more ASK1 inhibitors, optionally 0.1-95%, andoptionally 1-95%.

Salts, preferably sodium salts, of the inhibitors may be prepared withcarriers that protect the compound against rapid elimination from thebody, such as time release formulations or coatings. The formulationsmay further include other active compounds to obtain desiredcombinations of properties.

A. Formulations for Oral Administration

Oral pharmaceutical dosage forms may be as a solid, gel or liquid.Examples of solid dosage forms include, but are not limited to tablets,capsules, granules, and bulk powders. More specific examples of oraltablets include compressed, chewable lozenges and tablets that may beenteric-coated, sugar-coated or film-coated. Examples of capsulesinclude hard or soft gelatin capsules. Granules and powders may beprovided in non-effervescent or effervescent forms. Each may be combinedwith other ingredients known to those skilled in the art.

In certain embodiments, compounds according to the present invention areprovided as solid dosage forms, preferably capsules or tablets. Thetablets, pills, capsules, troches and the like may optionally containone or more of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders that may be used include, but are not limited to,microcrystalline cellulose, gum tragacanth, glucose solution, acaciamucilage, gelatin solution, sucrose, and starch paste.

Examples of lubricants that may be used include, but are not limited to,talc, starch, magnesium or calcium stearate, lycopodium and stearicacid.

Examples of diluents that may be used include, but are not limited to,lactose, sucrose, starch, kaolin, salt, mannitol, and dicalciumphosphate.

Examples of glidants that may be used include, but are not limited to,colloidal silicon dioxide.

Examples of disintegrating agents that may be used include, but are notlimited to, crosscarmellose sodium, sodium starch glycolate, alginicacid, corn starch, potato starch, bentonite, methylcellulose, agar andcarboxymethylcellulose.

Examples of coloring agents that may be used include, but are notlimited to, any of the approved certified water-soluble FD and C dyes,mixtures thereof, and water insoluble FD and C dyes suspended on aluminahydrate.

Examples of sweetening agents that may be used include, but are notlimited to, sucrose, lactose, mannitol and artificial sweetening agentssuch as sodium cyclamate and saccharin, and any number of spray-driedflavors.

Examples of flavoring agents that may be used include, but are notlimited to, natural flavors extracted from plants such as fruits andsynthetic blends of compounds that produce a pleasant sensation, suchas, but not limited to peppermint and methyl salicylate.

Examples of wetting agents that may be used include, but are not limitedto, propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether.

Examples of anti-emetic coatings that may be used include, but are notlimited to, fatty acids, fats, waxes, shellac, ammoniated shellac andcellulose acetate phthalates.

Examples of film coatings that may be used include, but are not limitedto, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the salt of the compound mayoptionally be provided in a composition that protects it from the acidicenvironment of the stomach. For example, the composition can beformulated in an enteric coating that maintains its integrity in thestomach and releases the active compound in the intestine. Thecomposition may also be formulated in combination with an antacid orother such ingredient.

When the dosage unit form is a capsule, it may optionally additionallycomprise a liquid carrier such as a fatty oil. In addition, dosage unitforms may optionally additionally comprise various other materials thatmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents.

Compounds according to the present invention may also be administered asa component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may optionally comprise, in addition to theactive compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors.

The compounds of the present invention may also be mixed with otheractive materials that do not impair the desired action, or withmaterials that supplement the desired action, such as antacids, H₂blockers, and diuretics. For example, if a compound is used for treatingasthma or hypertension, it may be used with other bronchodilators andantihypertensive agents, respectively.

Examples of pharmaceutically acceptable carriers that may be included intablets comprising compounds of the present invention include, but arenot limited to binders, lubricants, diluents, disintegrating agents,coloring agents, flavoring agents, and wetting agents. Enteric-coatedtablets, because of the enteric-coating, resist the action of stomachacid and dissolve or disintegrate in the neutral or alkaline intestines.Sugar-coated tablets may be compressed tablets to which different layersof pharmaceutically acceptable substances are applied. Film-coatedtablets may be compressed tablets that have been coated with polymers orother suitable coating. Multiple compressed tablets may be compressedtablets made by more than one compression cycle utilizing thepharmaceutically acceptable substances previously mentioned. Coloringagents may also be used in tablets. Flavoring and sweetening agents maybe used in tablets, and are especially useful in the formation ofchewable tablets and lozenges.

Examples of liquid oral dosage forms that may be used include, but arenot limited to, aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules andeffervescent preparations reconstituted from effervescent granules.

Examples of aqueous solutions that may be used include, but are notlimited to, elixirs and syrups. As used herein, elixirs refer to clear,sweetened, hydroalcoholic preparations. Examples of pharmaceuticallyacceptable carriers that may be used in elixirs include, but are notlimited to solvents. Particular examples of solvents that may be usedinclude glycerin, sorbitol, ethyl alcohol and syrup. As used herein,syrups refer to concentrated aqueous solutions of a sugar, for example,sucrose. Syrups may optionally further comprise a preservative.

Emulsions refer to two-phase systems in which one liquid is dispersed inthe form of small globules throughout another liquid. Emulsions mayoptionally be oil-in-water or water-in-oil emulsions. Examples ofpharmaceutically acceptable carriers that may be used in emulsionsinclude, but are not limited to non-aqueous liquids, emulsifying agentsand preservatives.

Examples of pharmaceutically acceptable substances that may be used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents.

Examples of pharmaceutically acceptable substances that may be used ineffervescent granules, to be reconstituted into a liquid oral dosageform, include organic acids and a source of carbon dioxide.

Coloring and flavoring agents may optionally be used in all of the abovedosage forms.

Particular examples of preservatives that may be used include glycerin,methyl and propylparaben, benzoic add, sodium benzoate and alcohol.

Particular examples of non-aqueous liquids that may be used in emulsionsinclude mineral oil and cottonseed oil.

Particular examples of emulsifying agents that may be used includegelatin, acacia, tragacanth, bentonite, and surfactants such aspolyoxyethylene sorbitan monooleate.

Particular examples of suspending agents that may be used include sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluentsinclude lactose and sucrose. Sweetening agents include sucrose, syrups,glycerin and artificial sweetening agents such as sodium cyclamate andsaccharin.

Particular examples of wetting agents that may be used include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurate,and polyoxyethylene lauryl ether.

Particular examples of organic acids that may be used include citric andtartaric acid.

Sources of carbon dioxide that may be used in effervescent compositionsinclude sodium bicarbonate and sodium carbonate. Coloring agents includeany of the approved certified water soluble FD and C dyes, and mixturesthereof.

Particular examples of flavoring agents that may be used include naturalflavors extracted from plants such fruits, and synthetic blends ofcompounds that produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603.

B. Injectables, Solutions, and Emulsions

The present invention is also directed to compositions designed toadminister the compounds of the present invention by parenteraladministration, generally characterized by subcutaneous, intramuscularor intravenous injection. Injectables may be prepared in anyconventional form, for example as liquid solutions or suspensions, solidforms suitable for solution or suspension in liquid prior to injection,or as emulsions.

Examples of excipients that may be used in conjunction with injectablesaccording to the present invention include, but are not limited towater, saline, dextrose, glycerol or ethanol. The injectablecompositions may also optionally comprise minor amounts of non-toxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents, stabilizers, solubility enhancers, and other such agents, suchas for example, sodium acetate, sorbitan monolaurate, triethanolamineoleate and cyclodextrins. Implantation of a slow-release orsustained-release system, such that a constant level of dosage ismaintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplatedherein. The percentage of active compound contained in such parenteralcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject.

Parenteral administration of the formulations includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as the lyophilized powders describedherein, ready to be combined with a solvent just prior to use, includinghypodermic tablets, sterile suspensions ready for injection, sterile dryinsoluble products ready to be combined with a vehicle just prior to useand sterile emulsions. The solutions may be either aqueous ornonaqueous.

When administered intravenously, examples of suitable carriers include,but are not limited to physiological saline or phosphate buffered saline(PBS), and solutions containing thickening and solubilizing agents, suchas glucose, polyethylene glycol, and polypropylene glycol and mixturesthereof.

Examples of pharmaceutically acceptable carriers that may optionally beused in parenteral preparations include, but are not limited to aqueousvehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, local anesthetics, suspending and dispersingagents, emulsifying agents, sequestering or chelating agents and otherpharmaceutically acceptable substances.

Examples of aqueous vehicles that may optionally be used include SodiumChloride Injection, Ringers Injection, Isotonic Dextrose Injection,Sterile Water Injection, Dextrose and Lactated Ringers Injection.

Examples of nonaqueous parenteral vehicles that may optionally be usedinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil.

Antimicrobial agents in bacteriostatic or fungistatic concentrations maybe added to parenteral preparations, particularly when the preparationsare packaged in multiple-dose containers and thus designed to be storedand multiple aliquots to be removed. Examples of antimicrobial agentsthat may be used include phenols or cresols, mercurials, benzyl alcohol,chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters,thimerosal, benzalkonium chloride and benzethonium chloride.

Examples of isotonic agents that may be used include sodium chloride anddextrose. Examples of buffers that may be used include phosphate andcitrate. Examples of antioxidants that may be used include sodiumbisulfate. Examples of local anesthetics that may be used includeprocaine hydrochloride. Examples of suspending and dispersing agentsthat may be used include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Examples of emulsifying agentsthat may be used include Polysorbate 80 (TWEEN 80). A sequestering orchelating agent of metal ions includes EDTA.

Pharmaceutical carriers may also optionally include ethyl alcohol,polyethylene glycol and propylene glycol for water miscible vehicles andsodium hydroxide, hydrochloric acid, citric acid or lactic acid for pHadjustment.

The concentration of an inhibitor in the parenteral formulation may beadjusted so that an injection administers a pharmaceutically effectiveamount sufficient to produce the desired pharmacological effect. Theexact concentration of an inhibitor and/or dosage to be used willultimately depend on the age, weight and condition of the patient oranimal as is known in the art.

Unit-dose parenteral preparations may be packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration should be sterile, as is known and practiced in the art.

Injectables may be designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the ASK1 inhibitor to the treatedtissue(s). The inhibitor may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment willbe a function of the location of where the composition is parenterallyadministered, the carrier and other variables that may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test data. It is to be noted that concentrations anddosage values may also vary with the age of the individual treated. Itis to be further understood that for any particular subject, specificdosage regimens may need to be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the formulations.Hence, the concentration ranges set forth herein are intended to beexemplary and are not intended to limit the scope or practice of theclaimed formulations.

The ASK1 inhibitor may optionally be suspended in micronized or othersuitable form or may be derivatized to produce a more soluble activeproduct or to produce a prodrug. The form of the resulting mixturedepends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease state and may be empiricallydetermined.

C. Lyophilized Powders

The compounds of the present invention may also be prepared aslyophilized powders, which can be reconstituted for administration assolutions, emulsions and other mixtures. The lyophilized powders mayalso be formulated as solids or gels.

Sterile, lyophilized powder may be prepared by dissolving the compoundin a sodium phosphate buffer solution containing dextrose or othersuitable excipient. Subsequent sterile filtration of the solutionfollowed by lyophilization under standard conditions known to those ofskill in the art provides the desired formulation. Briefly, thelyophilized powder may optionally be prepared by dissolving dextrose,sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose orother suitable agent, about 1-20%, preferably about 5 to 15%, in asuitable buffer, such as citrate, sodium or potassium phosphate or othersuch buffer known to those of skill in the art at, typically, aboutneutral pH. Then, a ASK1 inhibitor is added to the resulting mixture,preferably above room temperature, more preferably at about 30-35° C.,and stirred until it dissolves. The resulting mixture is diluted byadding more buffer to a desired concentration. The resulting mixture issterile filtered or treated to remove particulates and to insuresterility, and apportioned into vials for lyophilization. Each vial maycontain a single dosage or multiple dosages of the inhibitor.

D. Formulation for Topical Administration

The compounds of the present invention may also be administered astopical mixtures. Topical mixtures may be used for local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The ASK1 inhibitors may be formulated as aerosols for topicalapplication, such as by inhalation (see, U.S. Pat. Nos. 4,044,126,4,414,209, and 4,364,923, which describe aerosols for delivery of asteroid useful for treatment of inflammatory diseases, particularlyasthma). These formulations for administration to the respiratory tractcan be in the form of an aerosol or solution for a nebulizer, or as amicrofine powder for insufflation, alone or in combination with an inertcarrier such as lactose. In such a case, the particles of theformulation will typically have diameters of less than 50 microns,preferably less than 10 microns.

The inhibitors may also be formulated for local or topical application,such as for topical application to the skin and mucous membranes, suchas in the eye, in the form of gels, creams, and lotions and forapplication to the eye or for intracisternal or intraspinal application.Topical administration is contemplated for transdermal delivery and alsofor administration to the eyes or mucosa, or for inhalation therapies.Nasal solutions of the ASK1 inhibitor alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

E. Formulations for Other Routes of Administration

Depending upon the disease state being treated, other routes ofadministration, such as topical application, transdermal patches, andrectal administration, may also be used. For example, pharmaceuticaldosage forms for rectal administration are rectal suppositories,capsules and tablets for systemic effect. Rectal suppositories are usedherein mean solid bodies for insertion into the rectum that melt orsoften at body temperature releasing one or more pharmacologically ortherapeutically active ingredients. Pharmaceutically acceptablesubstances utilized in rectal suppositories are bases or vehicles andagents to raise the melting point. Examples of bases include cocoabutter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethyleneglycol) and appropriate mixtures of mono-, di- and triglycerides offatty acids. Combinations of the various bases may be used. Agents toraise the melting point of suppositories include spermaceti and wax.Rectal suppositories may be prepared either by the compressed method orby molding. The typical weight of a rectal suppository is about 2 to 3gm. Tablets and capsules for rectal administration may be manufacturedusing the same pharmaceutically acceptable substance and by the samemethods as for formulations for oral administration.

F. Examples of Formulations

The following are particular examples of oral, intravenous and tabletformulations that may optionally be used with compounds of the presentinvention. It is noted that these formulations may be varied dependingon the particular compound being used and the indication for which theformulation is going to be used.

ORAL FORMULATION Compound of the Present Invention 10-100 mg Citric AcidMonohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL

INTRAVENOUS FORMULATION Compound of the Present Invention 0.1-10 mgDextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL

TABLET FORMULATION Compound of the Present Invention 1% MicrocrystallineCellulose 73% Stearic Acid 25% Colloidal Silica 1%.

Dosage, Host and Safety

The compounds of the present invention are stable and can be usedsafely. In particular, the compounds of the present invention are usefulas ASK1 inhibitors for a variety of subjects (e.g., humans, non-humanmammals and non-mammals).

The optimal dose may vary depending upon such conditions as, forexample, the type of subject, the body weight of the subject, on theseverity of the condition, the route of administration, and specificproperties of the particular compound being used. Generally, acceptableand effective daily doses are amounts sufficient to effectively slow oreliminate the condition being treated. Typically, the daily dose fororal administration to an adult (body weight of about 60 kg) is about 1to 1000 mg, about 3 to 300 mg, or about 10 to 200 mg. It will beappreciated that the daily dose can be given in a single administrationor in multiple (e.g., 2 or 3) portions a day.

Kits and Articles of Manufacture Comprising ASK1 Inhibitors

The invention is also directed to kits and other articles of manufacturefor treating diseases associated with ASK1. It is noted that diseasesare intended to cover all conditions for which the ASK1 possess activitythat contributes to the pathology and/or symptomology of the condition.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one inhibitor of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one inhibitor of the presentinvention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

It is noted that the packaging material used in kits and articles ofmanufacture according to the present invention may form a plurality ofdivided containers such as a divided bottle or a divided foil packet.The container can be in any conventional shape or form as known in theart which is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.The container that is employed will depend on the exact dosage forminvolved, for example a conventional cardboard box would not generallybe used to hold a liquid suspension. It is feasible that more than onecontainer can be used together in a single package to market a singledosage form. For example, tablets may be contained in a bottle that isin turn contained within a box. Typically the kit includes directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral, topical, transdermaland parenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

One particular example of a kit according to the present invention is aso-called blister pack. Blister packs are well known in the packagingindustry and are being widely used for the packaging of pharmaceuticalunit dosage forms (tablets, capsules, and the like). Blister packsgenerally consist of a sheet of relatively stiff material covered with afoil of a preferably transparent plastic material. During the packagingprocess recesses are formed in the plastic foil. The recesses have thesize and shape of individual tablets or capsules to be packed or mayhave the size and shape to accommodate multiple tablets and/or capsulesto be packed. Next, the tablets or capsules are placed in the recessesaccordingly and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are individually sealed or collectively sealed, as desired, inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

Another specific embodiment of a kit is a dispenser designed to dispensethe daily doses one at a time in the order of their intended use.Preferably, the dispenser is equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter that indicates the number of dailydoses that has been dispensed. Another example of such a memory-aid is abattery-powered micro-chip memory coupled with a liquid crystal readout,or audible reminder signal which, for example, reads out the date thatthe last daily dose has been taken and/or reminds one when the next doseis to be taken.

Preparation of ASK1 Inhibitors

Various methods may be developed for synthesizing compounds according tothe present invention. Representative methods for synthesizing thesecompounds are provided in the Examples. It is noted, however, that thecompounds of the present invention may also be synthesized by othersynthetic routes that others may devise.

Synthetic Schemes for Compounds of the Present Invention

Compounds according to the present invention may be synthesizedaccording to the reaction schemes shown below. Other reaction schemescould be readily devised by those skilled in the art. It should also beappreciated that a variety of different solvents, temperatures and otherreaction conditions can be varied to optimize the yields of thereactions.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee P. G. M. Wuts and T. W. Greene in “Greene's Protective Groups inOrganic Synthesis” 4^(th) edition, John Wiley and Sons, 2007.

A general synthetic route for producing compounds of the presentinvention through the routes is shown in Scheme A. When commerciallyavailable 6-bromopyridin-3-amine is reacted with potassium thiocyanateand bromine in acetic acid, cyclized product A1 would be obtained.Subsequent reaction of A1 with an appropriate acid chloride in a solventsuch as DMA would produce the desired intermediate A2. If the acidchloride is an alkylcarboxy-substituted benzoyl chloride, the respectiveproduct of type A3 would be reacted further with excess of a Grignardreagent to give the desired alcohol intermediate A4.

Alternatively compounds of the present invention can be prepared throughthe route shown in Scheme B. Isobutyraldehyde can be α-arylated by ethylbromobenzoate under Pd-catalyzed conditions. Reduction of the aldehydeby NaBH₄ would give the corresponding alcohol B1. Protection of theprimary alcohol as the TBS ether followed by saponification would affordacid B3. Coupling of B3 with intermediate A1 (see Scheme A) using acoupling reagent such as TBTU would give intermediate B4. Afterfluoride-mediated deprotection of the TBS group, the desiredintermediate B5 would be obtained.

Alternatively compounds of the present invention can be prepared throughthe route shown in Scheme C. Commercially available carboxy-substitutedphenyl ketone C1 can be reacted with oxalyl chloride to give thecorresponding acid chloride C2, which is then reacted with intermediateA1 (Scheme A) to give intermediate C3. Subsequent reaction of C3 withTMSCF₃ followed by acidic workup would give the desired intermediate C4.

As shown in Scheme D, compounds of the present invention can be preparedfrom intermediates such as A2, described earlier in Schemes A-C. Wherering A is attached to the central scaffold via a carbon atom, palladiumcatalyzed coupling of a boronic acid or ester D1 would afford thedesired compound of type D2. Where ring A is attached via a nitrogen tothe central scaffold, a cyclic amine or imine D3 can be reacted atelevated temperatures, with or without copper iodide as a mediator, togive the desired product D4.

Alternatively compounds of the present invention can be prepared asshown in Scheme E. As in Scheme D, where ring A is attached to thecentral scaffold via a carbon atom, palladium catalyzed coupling ofintermediate A1 (Scheme A) and a boronic acid or ester D1 (Scheme D)would afford the desired intermediate of type E1; where ring A isattached via a nitrogen to the central scaffold, a cyclic amine or imineD3 (Scheme D) can be reacted with intermediate A1 (Scheme A) at elevatedtemperatures, with or without copper iodide as a mediator, to give thedesired the desired intermediate of type E2. After E1 or E2 is reactedwith an acid chloride or with an acid in the presence of a couplingreagent such as EDCI, the desired compounds E3 or E4, respectively,would be obtained.

Compounds of the present invention can be prepared as described inScheme F. Reacting commercially available 2,4-dichloro-5-nitropyrimidine(F1) with potassium isothiocyanate in acetic acid would giveintermediate F2. Suzuki coupling of F2 with a boronic acid or ester, orheating of F2 in the presence of a cyclic amine with or withoutcopper(I) iodide, would then produce intermediate of type F3. Reductionof the nitro group, followed by cyclization in situ, would give theprecursor F4, which can subsequently be converted to the desiredcompounds by acylation with an acid chloride, for example.

General Procedures for the Preparation of the Compounds of the Invention

It will be readily recognized that certain compounds according to thepresent invention have atoms with linkages to other atoms that confer aparticular stereochemistry to the compound (e.g., chiral centers). It isrecognized that synthesis of compounds according to the presentinvention may result in the creation of mixtures of differentstereoisomers (i.e., enantiomers and diastereomers). Unless a particularstereochemistry is specified, recitation of a compound is intended toencompass all of the different possible stereoisomers.

Compounds according to the present invention can also be prepared astheir individual stereoisomers by reacting a racemic mixture of thecompound with an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomer. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of compounds,dissociable complexes are preferred (e.g., crystalline diastereoisomericsalts).

Compounds according to the present invention can also be prepared as apharmaceutically acceptable acid addition salt by reacting the free baseform of the compound with a pharmaceutically acceptable inorganic ororganic acid. Alternatively, a pharmaceutically acceptable base additionsalt of a compound can be prepared by reacting the free acid form of thecompound with a pharmaceutically acceptable inorganic or organic base.Inorganic and organic acids and bases suitable for the preparation ofthe pharmaceutically acceptable salts of compounds are set forth in thedefinitions section of this Application. Alternatively, the salt formsof the compounds can be prepared using salts of the starting materialsor intermediates.

The free acid or free base forms of the compounds can be prepared fromthe corresponding base addition salt or acid addition salt form. Forexample, a compound in an acid addition salt form can be converted tothe corresponding free base by treating with a suitable base (e.g.,ammonium hydroxide solution, sodium hydroxide, and the like). A compoundin a base addition salt form can be converted to the corresponding freeacid by treating with a suitable acid (e.g., hydrochloric acid, etc).

The N-oxides of compounds according to the present invention can beprepared by methods known to those of ordinary skill in the art. Forexample, N-oxides can be prepared by treating an unoxidized form of thecompound with an oxidizing agent (e.g., trifluoroperacetic acid,permaleic acid, perbenzoic acid, peracetic acid,meta-chloroperoxybenzoic acid, or the like) in a suitable inert organicsolvent (e.g., a halogenated hydrocarbon such as dichloromethane) atapproximately 0° C. Alternatively, the N-oxides of the compounds can beprepared from the N-oxide of an appropriate starting material.

Compounds in an unoxidized form can be prepared from N-oxides ofcompounds by treating with a reducing agent (e.g., sulfur, sulfurdioxide, triphenyl phosphine, lithium borohydride, sodium borohydride,phosphorus trichloride, tribromide, or the like) in an suitable inertorganic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or thelike) at 0 to 80° C.

Prodrug derivatives of the compounds can be prepared by methods known tothose of ordinary skill in the art (e.g., for further details seeSaulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p. 1985). For example, appropriate prodrugs can be prepared byreacting a non-derivatized compound with a suitable carbamylating agent(e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, orthe like).

Protected derivatives of the compounds can be made by methods known tothose of ordinary skill in the art. A detailed description of thetechniques applicable to the creation of protecting groups and theirremoval can be found in P. G. M. Wuts and T. W. Greene, “Greene'sProtecting Groups in Organic Synthesis”, 4^(th) edition, John Wiley &Sons, Inc. 2007.

Compounds according to the present invention may be convenientlyprepared, or formed during the process of the invention, as solvates(e.g., hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

μL (microliters) Ac (acetyl) atm (atmosphere) ATP (AdenosineTriphosphatase) BOC (tert-butyloxycarbonyl) BOP(bis(2-oxo-3-oxazolidinyl)phosphinic chloride) BSA (Bovine SerumAlbumin) CBZ (benzyloxycarbonyl) CDI (1,1-carbonyldiimidazole) DCC(dicyclohexylcarbodiimide) DCE (dichloroethane) DCM (dichloromethane)DMAP (4-dimethylaminopyridine) DME (1,2-dimethoxyethane) DMF(N,N-dimethylformamide) DMPU (N,N′-dimethylpropyleneurea) DMSO(dimethylsulfoxide) EDCI (ethylcarbodiimide hydrochloride) EDTA(Ethylenediaminetetraacetic acid) Et (ethyl) Et₂O (diethyl ether) EtOAc(ethyl acetate) FMOC (9-fluorenylmethoxycarbonyl) g (grams) h (hours)HOAc or AcOH (acetic acid) HOBT (1-hydroxybenzotriazole) HOSu(N-hydroxysuccinimide) HPLC (high pressure liquid chromatography) Hz(Hertz) i.v. (intravenous) IBCF (isobutyl chloroformate) i-PrOH(isopropanol) L (liters) M (molar) mCPBA (meta-chloroperbenzoic acid) Me(methyl) MeOH (methanol) mg (milligrams) MHz (megahertz) min (minutes)mL (milliliters) mM (millimolar) mmol (millimoles) mol (moles) MOPS(Morpholinepropanesulfonic acid) mp (melting point) NaOAc (sodiumacetate) OMe (methoxy) psi (pounds per square inch) RP (reverse phase)r.t. (ambient temperature) SPA (Scintillation Proximity Assay) TBAF(tetra-n-butylammonium fluoride) TBS (t-butyldimethylsilyl) TBSOTf(t-butyldimethylsilyl trifluoromethanesulfonate) TBTU(O-(benzotriazol-1-yl)-N,N,N′,N′- tBu (tert-butyl) tetramethyluroniumtetrafluoroborate) TEA (triethylamine) TFA (trifluoroacetic acid) TFAA(trifluoroacetic anhydride) THF (tetrahydrofuran) TIPS(triisopropylsilyl) TLC (thin layer chromatography) TMS (trimethylsilyl)TMSE (2-(trimethylsilyl)ethyl) Tr (retention time) Brij35(polyoxyethyleneglycol dodecyl ether)

All references to ether or Et₂O are to diethyl ether; and brine refersto a saturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at RT unless otherwise noted.

¹H NMR spectra were recorded on a Bruker Avance 400. Chemical shifts areexpressed in parts per million (ppm). Coupling constants are in units ofHertz (Hz). Splitting patterns describe apparent multiplicities and aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), br (broad).

Low-resolution mass spectra (MS) and compound purity data were acquiredon a Waters ZQ LC/MS single quadrupole system equipped with electrosprayionization (ESI) source, UV detector (220 and 254 nm), and evaporativelight scattering detector (ELSD). Thin-layer chromatography wasperformed on 0.25 mm E. Merck silica gel plates (60F-254), visualizedwith UV light, 5% ethanolic phosphomolybdic acid, Ninhydrinorp-anisaldehyde solution. Flash column chromatography was performed onsilica gel (230-400 mesh, Merck).

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as the AldrichChemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma(St. Louis, Mo.), or may be prepared by methods well known to a personof ordinary skill in the art, following procedures described in suchstandard references as Fieser and Fieser's Reagents for OrganicSynthesis, vols. 1-23, John Wiley and Sons, New York, N.Y., 2006; Rodd'sChemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier SciencePublishers, 1998; Organic Reactions, vols. 1-68, John Wiley and Sons,New York, N.Y., 2007; March J.: Advanced Organic Chemistry, 5th ed.,2001, John Wiley and Sons, New York, N.Y.; and Larock: ComprehensiveOrganic Transformations, 2^(nd) edition, John Wiley and Sons, New York,1999. The entire disclosures of all documents cited throughout thisapplication are incorporated herein by reference.

Various methods for separating mixtures of different stereoisomers areknown in the art. For example, a racemic mixture of a compound may bereacted with an optically active resolving agent to form a pair ofdiastereoisomeric compounds. The diastereomers may then be separated inorder to recover the optically pure enantiomers. Dissociable complexesmay also be used to resolve enantiomers (e.g., crystallinediastereoisomeric salts). Diastereomers typically have sufficientlydistinct physical properties (e.g., melting points, boiling points,solubilities, reactivity, etc.) and can be readily separated by takingadvantage of these dissimilarities. For example, diastereomers cantypically be separated by chromatography or by separation/resolutiontechniques based upon differences in solubility. A more detaileddescription of techniques that can be used to resolve stereoisomers ofcompounds from their racemic mixture can be found in Jean Jacques, AndreCollet, and Samuel H. Wilen, Enantiomers, Racemates and Resolutions,John Wiley & Sons, Inc. (1981).

Diastereomers have distinct physical properties (e.g., melting points,boiling points, solubilities, reactivity, etc.) and can be readilyseparated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques, Andre Collet, and Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

Chiral components can be separated and purified using any of a varietyof techniques known to those skilled in the art. For example, chiralcomponents can be purified using supercritical fluid chromatography(SFC). In one particular variation, chiral analytical SFC/MS analysesare conducted using a Berger analytical SFC system (AutoChem, Newark,Del.) which consists of a Berger SFC dual pump fluid control module witha Berger FCM 1100/1200 supercritical fluid pump and FCM 1200 modifierfluid pump, a Berger TCM 2000 oven, and an Alcott 718 autosampler. Theintegrated system can be controlled by BI-SFC Chemstation softwareversion 3.4. Detection can be accomplished with a Waters ZQ 2000detector operated in positive mode with an ESI interface and a scanrange from 200-800 Da with 0.5 second per scan. Chromatographicseparations can be performed on a ChiralPak AD-H, ChiralPak AS-H,ChiralCel OD-H, or ChiralCel OJ-H column (5μ, 4.6×250 mm; ChiralTechnologies, Inc. West Chester, Pa.) with 10 to 40% methanol as themodifier and with or without ammonium acetate (10 mM). Any of a varietyof flow rates can be utilized including, for example, 1.5 or 3.5 mL/minwith an inlet pressure set at 100 bar. Additionally, a variety of sampleinjection conditions can be used including, for example, sampleinjections of either 5 or 10 μL in methanol at 0.1 mg/mL inconcentration.

In another variation, preparative chiral separations are performed usinga Berger MultiGram II SFC purification system. For example, samples canbe loaded onto a ChiralPak AD column (21×250 mm, 10μ). In particularvariations, the flow rate for separation can be 70 mL/min, the injectionvolume up to 2 mL, and the inlet pressure set at 130 bar. Stackedinjections can be applied to increase the efficiency.

Descriptions of the syntheses of particular compounds according to thepresent invention based on the above reaction schemes and variationsthereof are set forth in the Example section.

Assaying the Biological Activity of the Compounds of the Invention

The inhibitory effect of the compound of the invention on ASK1 may beevaluated by a variety of binding assays and functional assays.

ASK1 protein for the assay may be prepared by standard PCR cloning andexpression in a vector. Example A discloses such a method of preparingthe enzyme. However, it should be noted that ASK1 is commerciallyavailable through Millipore (Cat. #14-606).

The inhibitory effect of the compound of the invention on ASK1 may beevaluated by evaluating the phosphorylating activity of the enzyme on aknown substrate with or without the presence of the test compound.Example B provides such an assay where myelin basic protein (Wako) isused as substrate and detection is by scintillation counting. It shouldbe understood other substrates and detection mechanism may be used. Acommercially available a kit, Cisbio's HTRF® KinEASE™ STK kit, has shownto be useful for evaluating ASK1 activity. The assay uses ananti-phosphoseric specific, Eu3+-Cryptate labeled antibody to mark thephosphorylated product of ASK1 on a biotinylated kinase substrate, anddetection is by time resolved fluorescence using XL665 labeledstreptavidin. The fluorescence intensity is proportional to the amountof product formation. Example C provides the assay protocol.

IC₅₀ values of selected compounds of the invention were measured usingthe assay described in Example B. Some of the exemplified compounds wereshown to have IC₅₀ of greater than 1 μM, some others less than about 1μM, and most others of the compounds have an IC₅₀ value of less thanabout 0.1 μM. For example, Compound 30 exhibits an IC₅₀ value of 310 nM.The IC₅₀ values of the exemplified compounds of the present inventionare given in Table 1.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the compounds, compositions,kits, and methods of the present invention without departing from thespirit or scope of the invention. Thus, it is intended that the presentinvention cover the modifications and variations of this inventionprovided they come within the scope of the appended claims and theirequivalents.

EXAMPLES Example 1 Preparation of intermediatesN-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(1D) andN-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(trifluoromethyl)benzamide (1E)

Step A: Commercially available 6-bromopyridin-3-amine (1A, 20 g, 1.0equivalent) was added in portions to a solution of potassium thiocyanate(5.0 equivalents) in acetic acid (0.4 M) at −5° C. After addition, themixture was cooled to −15° C., and a solution of Br₂ (1.3 equivalent) inacetic acic (9.4 M) was added drop wise via an additional funnel. Themixture was then warmed to room temperature and stirred for 12 h. Theresulting precipitate was filtered; 100 mL EtOAc and 200 mL H₂O wereadded to the filtrate and then 200 mL of solvent was removed in vacuo.The residue was stirred in ice bath for 10 minutes, and then theresulting precipitate was collected by filtration and washed twice withcold 10% MeOH in Et₂O. The filtrate was concentrated and the product wascrystallized in ice bath to obtain a second crop of product afterwashing twice with cold 10% MeOH in Et₂O. The product 1B (77%) wasobtained as a brown solid after drying under vacuum, and then usedwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.94 (br.s., 1H) 7.44 (d, J=8.34 Hz, 1H) 7.57 (d, J=8.34 Hz, 1H) 8.04 (br. s.,1H); ESI-MS: m/z 230.0 (M+H)⁺.

Step B: 5-bromothiazolo[5,4-b]pyridin-2-amine (1B, 5.0 g, 1.0equivalent) was dissolved in DMA (0.9 M), and then followed by additionof methyl 4-(chlorocarbonyl)benzoate (2.0 equivalent). The mixture wasthen heated to 50° C. for 1 h. After the mixture was cooled to roomtemperature, a 70 mL solution of 5% MeOH in Et₂O was added. Afterstirring for 10 minutes, the resulting fine precipitate was collected byfiltration. The filtered caked was taken into a 150 mL solution of 30%MeOH in Et₂O, and stirred at 30° C. for 10 minutes. The mixture was thenfiltered and the collected solid was washed twice with cold solution of10% MeOH in Et₂O. After drying under vacuum, the product 1C (60%) wasobtained as a light yellow solid, and was used in the next step withoutfurther purification. 1C: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.89 (s, 3H)7.67-7.74 (m, 1H) 8.05-8.14 (m, 3H) 8.22 (d, J=8.84 Hz, 2H) 13.33 (br.s., 1H); ESI-MS: m/z 392.0 (M+H)⁺.

Step C: Methyl 4-(5-bromothiazolo[5,4-b]pyridin-2-ylcarbamoyl)benzoate(1C, 1.4 g, 1.0 equivalent) was dissolved in THF (0.14 M) and thencooled in ice bath. Methyl magnesium bromide (5.0 equivalents) was addedslowly, and the mixture was continued to stir at 0° C. for 3 h. Thencold aqueous saturated NH₄Cl was added, and the mixture was extractedtwice with EtOAc. Combined organic layers were dried over Na₂SO₄,filtered and concentrated. 20 mL of MeOH was added to the residue andthen heated to 50° C. for 10 minutes. After the mixture was cooled toroom temperature, the resulting precipitate was collected by filtration.After drying under vacuum, the product 1D (54%) was obtained as anoff-white solid, and was used in the next step without furtherpurification. 1D: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46 (s, 6H) 5.23 (s,1H) 7.67 (d, J=8.59 Hz, 2H) 7.72 (d, J=8.34 Hz, 1H) 8.07-8.14 (m, 3H)13.09 (br. s., 1H); ESI-MS: m/z 392.0 (M+H)⁺.

N-(5-Bromothiazolo[5,4-b]pyridin-2-yl)-4-(trifluoromethyl)benzamide (1E)was prepared using a procedure analogous to that described in connectionwith 1C except 4-(trifluoromethyl)benzoyl chloride was used as astarting material (yield=29%, tan color solid). 1E: ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.74 (d, J=8.34 Hz, 1H) 7.97 (d, J=8.34 Hz, 2H) 8.14 (d,J=8.59 Hz, 1H) 8.31 (d, J=8.08 Hz, 2H) 13.41 (br. s., 1H); ESI-MS: m/z402.0 (M+H)⁺.

Example 2 Preparation of intermediateN-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide(2F)

Step A: Anhydrous cesium carbonate (7.8 g, 1.2 equivalents) wassuspended in dixoane (0.25 M). Ethyl 4-bromobenzoate 2A (1.0equivalent), isobutyraldehyde (2.0 equivalents), Pd(OAc)₂ (0.05equivalent) and tri-tert-butylphosphine (0.1 equivalent) were added. Theresulting mixture was heated to 110° C. for 2 h. After cooling, waterwas added and the mixture was extracted with ethyl acetate. Combinedorganic layers were dried over MgSO₄, filtered and concentrated. Thecrude product was purified by chromatography (SiO₂) to give 2B (15%) asa colorless oil: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32-1.44 (m, 9H)2.04 (s, 1H) 3.65 (d, J=6.2 Hz, 2H) 4.37 (q, J=7.2 Hz, 2H), 7.41-7.52(m, 2H), 7.96-8.06 (m, 2H).

Step B: To a solution of ethyl 4-(1,1-dimethyl-2-oxoethyl)benzoate (2B,680 mg, 1.0 equivalent) and 2,6-lutidine (2.0 equivalents) in CH₂Cl₂(0.03 M) was added TBSOTf (1.5 equivalents) at 0° C. With gradualwarming to room temperature, the reaction mixture was stirred for 1 h.Water was then added, and the mixture was extracted with CH₂Cl₂.Combined organic layers were dried over MgSO₄, filtered andconcentrated. The crude product was purified by chromatography (SiO₂) togive 2C (99%) as a colorless oil: ¹H NMR (CHLOROFORM-d) δ ppm-0.07 (s,6H) 0.83 (s, 9H) 1.31 (s, 6H) 1.39 (t, J=7.2 Hz, 3H) 3.55 (s, 2H) 4.36(q, J=7.2 Hz, 2H) 7.44 (d, J=8.4 Hz, 2H) 7.96 (d, J=8.4 Hz, 2H).

Step C: To a solution of ethyl4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)benzoate (2C,1.0 g, 1.0 equivalents) in a 3:1 mixture of THF/MeOH (0.78 M) was added0.9 M aqueous solution of KOH (2.9 equivalents). The reaction mixturewas heated to 70° C. for 1 h. After stirring, the solvents wereevaporated, and the residue was acidified with dilute aqueous HCl andthen extracted with CH₂Cl₂. Combined organic layers were dried overMgSO₄, filtered and concentrated. The crude product was purified bychromatography (SiO₂) to give 2D (82%) as a white solid: ¹H NMR(CHLOROFORM-d) δ ppm -0.07 (s, 6H) 0.82 (s, 9H) 1.32 (s, 6H) 3.56 (s,2H) 7.47 (d, J=8.7 Hz, 2H) 8.01 (d, J=8.7 Hz, 2H).

Step D: 4-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)benzoicacid (2D, 3.0 g, 1.0 equivalent) was dissolved in DMF, then followed byaddition of TBTU (1.2 equivalent). The mixture was stirred at roomtemperature for 2 h, then 5-bromothiazolo[5,4-b]pyridin-2-amine (1.2equivalent) was added, and followed by Et₃N (3.0 equivalents), and thiswas heated to 60° C. for 12 h. After stirring, water was added andfollowed by extraction with EtOAc twice. The combined organic layerswere dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by chromatography (SiO₂, gradient of 5 to 10% EtOAc/hexanes) togive 2E (60%) as a white solid: ESI-MS: m/z 520.0 (M+H)⁺.

Step E: N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)benzamide(2E, 1.9 g, 1.0 equivalent) was dissolved in THF (0.4 M). Cooled mixturein ice bath, and followed by a slow addition of TBAF (1.0M THF solution,6.5 equivalents). After addition, mixture was warmed to room temperatureand then heated to 60° C. for 3 h. After stirring, water was added andfollowed by extraction with EtOAc twice. The combined organic layerswere dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by chromatography (SiO₂, gradient of 1 to 5% MeOH/CH₂Cl₂) togive 2F (60%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26 (s,6H) 3.48 (s, 2H) 4.77 (br. s., 1H) 7.57 (d, J=8.59 Hz, 2H) 7.72 (d,J=8.34 Hz, 1H) 8.05-8.16 (m, 3H) 13.08 (s, 1H); ESI-MS: m/z 406.0(M+H)⁺.

Example 3 Preparation of intermediates4-acetyl-N-(5-bromothiazolo[5,4-b]pyridin-2-yl)benzamide (3C) andN-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide(3D)

Step A: 4-acetylbenzoic acid 3A (500 mg, 1.0 equivalent) was dissolvedin DCM (0.3 M), and then followed by addition of oxalyl chloride (1.2equivalent) and DMF (0.3 equivalent). The mixture was stirred at roomtemperature for 1 h. Volatiles were removed in vacuo. The residue 3B wasobtained as a white solid and was used without further purification. 3B:ESI-MS: m/z 183.0 (M+H)⁻.

Step B: 4-acetylbenzoyl chloride (3B, 560 mg, 1.0 equivalent) wasdissolved in DMA (0.15 M). Methyl 4-(chlorocarbonyl)benzoate (2.0equivalent) was then added. The mixture was heated to 50° C. for 12 h,followed by addition of water and extraction with EtOAc twice. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by chromatography(SiO₂, gradient of 5 to 20% EtOAc/Hex) to give 3C (16%) as a tan solid:¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.66 (s, 3 H) 7.73 (d, J=8.59 Hz, 1H)8.08-8.17 (m, 3H) 8.25 (d, J=8.84 Hz, 2H) 13.36 (br. s., 1H); ESI-MS:m/z 376.0 (M+H)⁺.

Step C: 4-acetyl-N-(5-bromothiazolo[5,4-b]pyridin-2-yl)benzamide (3C, 60mg, 1.0 equivalent) was dissolved in THF (0.1 M), and then followed bytrimethyl(trifluoromethyl)silane (2.0 eq) and TBAF (1.0 M THF solution,0.1 equivalent). The mixture was stirred at room temperature for 12 h,and then followed by addition of 0.5 mL 5 N aqueous HCl and stirred for12 h. After stirring, water was added and the mixture was extracted withEtOAc twice. The residue was isolated by preparatory LCMS to give 3D(14%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.66 (s, 3H)7.72-7.76 (m, 1H) 8.10-8.16 (m, 3H) 8.25 (d, J=8.34 Hz, 2H) 13.36 (br.s., 1H); ESI-MS: m/z 446.0 (M+H)⁺.

Example 4 Preparation of intermediatesN-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-tert-butylbenzamide (4A) and4-tert-butyl-N-(5-chlorothiazolo[5,4-b]pyridin-2-yl)benzamide (4B)

5-bromothiazolo[5,4-b]pyridin-2-amine (1B, 1.0 g, 1.0 equivalent) wasdissolved in DMA (0.36 M), and then 4-tert-butylbenzoyl chloride (2.0equivalents) was added. The mixture was heated to 50° C. under N₂ for 7h. After cooling to room temperature, the crude mixture was addedsaturated aqueous NaHCO₃ and extracted with EtOAc three times. Combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by chromatography (SiO₂, gradient of 5 to 20%EtOAc/hexanes) to give 4A (44%) as a white solid: ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.33 (s, 9H) 7.61 (d, J=8.34 Hz, 2H) 7.72 (d, J=8.34 Hz,1H) 8.10 (dd, J=8.34, 3.03 Hz, 3H) 13.08 (s, 1H); ESI-MS: m/z 390.0(M+H)⁺.

4-tert-Butyl-N-(5-chlorothiazolo[5,4-b]pyridin-2-yl)benzamide (4B) wasprepared as a white solid (yield=20%) using a procedure analogous tothat described above for 4A except that5-chlorothiazolo[5,4-b]pyridin-2-amine (1B′) was used as startingmaterial. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 7.60 (dd, J=8.46,1.64 Hz, 3H) 8.10 (d, J=8.34 Hz, 2H) 8.20 (d, J=8.34 Hz, 1H) 13.08 (s,1H); ESI-MS: m/z 346.0 (M+H)⁺.

Example 5 Preparation ofN-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-cyclopropylbenzamide(5)

Step A: To a microwave vial, 5-bromothiazolo[5,4-b]pyridin-2-amine (1B,100 mg, 1.0 equivalent),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5A, 2.0equivalent), Na₂CO₃ (4.0 equivalents), DMF (0. 15 M) and H₂O (0.73 M)were added. While mixture was under N₂, Pd(PPh₃)₄ was added and themixture was then heated in a microwave for 3 h at 150° C. The crudemixture was filtered, and purified by preparatory LCMS. Intermediate5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-amine (5B) was obtained as awhite solid. ESI-MS: m/z 218.0 (M+H)⁺.

Step B: 5B (25.0 mg, 1.0 equivalent) and 4-cyclopropylbenzoic acid (1.1equivalent) were dissolved in DMF, followed by addition of HOBt (1.0equivalent), EDC (1.0 equivalent), Et₃N (2.0 equivalents). The mixturewas stirred for 12 h at room temperature. The crude mixture was filteredand purified by LCMS to give the titled compound 5 as a white solid: ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.77-0.87 (m, 2H) 1.04-1.13 (m, 2H)2.01-2.10 (m, 1H) 7.28 (d, J=8.34 Hz, 2H) 7.68 (t, J=7.58 Hz, 1H)7.82-7.91 (m, 3H) 7.99 (d, J=8.34 Hz, 2H) 8.47 (s, 1H) 9.03 (s, 1H);ESI-MS: m/z 362.0 (M+H)⁺.

Example 6 Preparation ofN-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide (6)

Step A: 5-bromothiazolo[5,4-b]pyridin-2-amine (1B, 200 mg, 1.0equivalent) and nicotinoyl chloride hydrochloride (6A, 2.0 equivalents)was added pyridine (0.17 M) and was stirred at room temperature for 12h. The solvent was removed in vacuo, and MeOH/Et₂O was added to theresidue and cooled in ice bath for 10 minutes. The resulting precipitatewas collected by filtration and washed twice with cold 10% MeOH in Et₂Oto afford compound 6B (70%) as a white solid: ESI-MS: m/z 335.0 (M+H)⁺.

Step B: N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide(5C) was prepared using a procedure analogous to that described in StepA in Example 5 except thatN-(5-bromothiazolo[5,4-b]pyridin-2-yl)nicotinamide (6B) was used asstarting material instead of 1B. After cooling to room temperature, thecrude mixture was filtered and purified by LCMS to give the TFA salt ofthe titled compound 6 (21%) as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆)δ ppm 7.64 (dd, J=7.96, 4.93 Hz, 1H) 7.85 (d, J=8.59 Hz, 1H) 8.13 (d,J=8.34 Hz, 1H) 8.29 (s, 2H) 8.41-8.54 (m, 1H) 8.84 (d, J=4.80 Hz, 1H)9.26 (s, 1H) 13.19 (br. s., 1H); ESI-MS: m/z 323.0 (M+H)⁻.

Example 7 Preparation ofN-(5-(1H-imidazol-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(7)

N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(1D, 50 mg, 1.0 equivalent), imidazole (2.0 equivalents), CuI (0.1equivalent), K₂CO₃ (2.0 equivalents) were dissolved in DMF (0.06 M) andheated to 150° C. under N₂ for 12 h. After cooling to room temperature,the crude mixture was filtered and purified by LCMS to give the TFA saltof the titled compound 7 (33%) as a yellow solid: ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.48 (s, 6H) 7.68 (d, J=8.34 Hz, 2H) 7.85 (br. s., 1H)8.02-8.21 (m, 3H) 8.48 (d, J=8.84 Hz, 2H) 9.81 (br. s., 1H) 13.18 (br.s., 1H); ESI-MS: m/z 380.0 (M+H)⁺.

Example 8 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(8)

N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(1D, 50 mg, 1.0 equivalent) and pyrrolidine (3.0 equivalents) weredissolved in NMP (0.06 M) under N₂ in microwave vial. The mixture washeated to 180° C. for 20 minutes. After cooling to room temperature, thecrude mixture was filtered and purified by LCMS to give the TFA salt ofthe titled compound 8 (35%) as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.46 (s, 6H) 1.92-2.02 (m, 4H) 3.40-3.50 (m, 4H) 6.61 (d, J=9.09Hz, 1H) 7.63 (d, J=8.59 Hz, 2H) 7.86 (d, J=9.09 Hz, 1H) 8.05(d, J=8.84Hz, 2H) 12.53 (s, 1H); ESI-MS: m/z 383.0 (M+H)⁺.

Example 9 Preparation ofN-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-tert-butylbenzamide(9)

The titled compound,N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-tert-butylbenzamide(9), was prepared using a procedure analogous to that described in StepA of Example 5 exceptN-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-tert-butylbenzamide (4A, 100mg, 1.0 equivalent) was used. After heating in microwave at 160° C. for1.5 h, the crude was cooled to room temperature. Then the crude mixturewas filtered and purified by LCMS to give the TFA salt of the titledcompound 9 (59%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34(s, 9H) 7.61 (d, J=8.34 Hz, 2H) 7.84 (d, J=8.34 Hz, 1H) 8.10 (d, J=7.83Hz, 3H) 8.29 (br. s., 2H) 12.88 (s, 1H); ESI-MS: m/z 378.0 (M+H)⁺.

Example 10 Preparation of4-tert-butyl-N-(5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(10)

The titled compound was prepared using a procedure analogous to thatdescribed in connection with 9 (Example 9). To a microwave vial,N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-tert-butylbenzamide (4A, 120mg, 1.0 equivalent) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.2 equivalent)in dioxane (0.17 M) and DMF (0.51 M) was stirred in N₂. Followed byaddition of Na₂CO₃ (2 M aqueous solution, 8.0 equivalents) andPdCl₂(dppf)/DCM adduct (0.05 equivalent). The mixture was heated at 120°C. for 10 minutes. After cooling to room temperature, the crude mixturewas added saturated aqueous NaHCO₃ and extracted with EtOAc twice.Combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by chromatography (SiO₂,gradient of 1 to 10% MeOH/CH₂Cl₂) to give the titled compound 10 (50%)as a tan solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 7.61 (d,J=8.59 Hz, 2H) 8.08-8.16 (m, 4H) 8.27 (d, J=1.77 Hz, 2H) 8.72 (d, J=6.06Hz, 2H) 13.07 (s, 1H); ESI-MS: m/z 389.0 (M+H)⁺.

Example 11 Preparation ofN-(5-(1H-imidazol-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-tert-butylbenzamide(11)

The titled compound (yield=21%) was prepared using a procedure analogousto that described in connection with 7 (Example 7) except 4A was used asa starting material. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 7.16(s, 1H) 7.60 (d, J=8.34 Hz, 2H) 7.94 (d, J=8.59 Hz, 1H) 8.04 (s, 1H)8.11 (d, J=8.34 Hz, 2H) 8.33 (d, J=8.59 Hz, 1H) 8.60 (s, 1H) 13.03 (br.s., 1H); ESI-MS: m/z 378.0 (M+H)⁺.

Example 12 Preparation ofN-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(12)

The titled compound (yield=12%) was prepared using a procedure analogousto that described in connection with 9 (Example 9) except 1D (Example 1)was used as a starting material. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46(s, 6H) 7.66 (d, J=8.34 Hz, 2H) 7.83 (d, J=8.59 Hz, 1H) 8.10 (dd,J=8.46, 2.15 Hz, 3H) 8.30 (br. s., 2H) 12.88 (br. s., 1H); ESI-MS: m/z380.0 (M+H)⁺.

Example 13 Preparation ofN-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide(13)

The titled compound (yield=37%) was prepared using a procedure analogousto that described in connection with 9 (Example 9) except 2F (Example 2)and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole wereused as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (s, 6H)3.48 (s, 3H) 7.57 (d, J=8.34 Hz, 2H) 7.83 (d, J=8.59 Hz, 1H) 8.02-8.17(m, 3H) 8.28 (s, 2H) 12.88 (s, 1H); ESI-MS: m/z 394.0 (M+H)⁺.

Example 14 Preparation ofN-(5-(3,5-dimethyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(14)

The titled compound (yield=25%, white solid) was prepared using aprocedure analogous to that described in connection with 9 (Example 9)except 1D (Example 1) and3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewere used as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46(s, 6H) 2.40 (s, 6H) 7.54 (d, J=8.34 Hz, 1H) 7.66 (d, J=8.34 Hz, 2H)8.04-8.19 (m, 3H) 12.89 (br. s., 1H); ESI-MS: m/z 408.0 (M+H)⁺.

Example 15 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(15)

The titled compound (yield=11%, white solid) was prepared using aprocedure analogous to that described in connection with 9 (Example 9)except 1D (Example 1) and3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewere used as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46(s, 6H) 2.58 (s, 3H) 7.66 (d, J=8.59 Hz, 2H) 7.74 (d, J=8.59 Hz, 1H)8.09 (d, J=8.59 Hz, 4H) 12.86 (s, 1H); ESI-MS: m/z 394.0 (M+H)⁺.

Example 16 Preparation ofN-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-acetylbenzamide(16)

The titled compound (yield=19%, yellow solid) was prepared using aprocedure analogous to that described in connection with 9 (Example 9)except 3C (Example 3) was used instead. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.66 (s, 3H) 7.85 (d, J=8.59 Hz, 1H) 8.12 (d, J=8.34 Hz, 3H) 8.19-8.36(m, 4H) 13.16 (br. s., 1H); ESI-MS: m/z 364.0 (M+H)⁺.

Example 17 Preparation ofN-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide(17)

The titled compound (yield=23%) was prepared using a procedure analogousto that described in connection with 9 (Example 9) except 3D (Example 3)was used as a starting material. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.75(s, 3H) 6.83 (s, 1H) 7.82 (dd, J=19.58, 8.46 Hz, 3H) 8.09-8.20 (m, 3H)8.28 (br. s., 1H) 13.00 (s, 1H); ESI-MS: m/z 434.0 (M+H)⁺.

Example 18 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(1-methyl-1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(18)

The titled compound (yield=4%) was prepared using a procedure analogousto that described in connection with 9 (Example 9) except 1D (Example 1)and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewere used as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47(s, 6H) 4.20 (s, 3H) 6.86 (d, J=1.26 Hz, 1H) 7.52 (d, J=1.26 Hz, 1H)7.67 (d, J=8.08 Hz, 2H) 7.92 (d, J=8.59 Hz, 1H) 8.11 (d, J=8.34 Hz, 2H)8.23 (d, J=8.34 Hz, 1H) 13.03 (s, 1H); ); ESI-MS: m/z 394.0 (M+H)⁺.

Example 19 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(19)

The titled compound (yield=37%, white solid) was prepared using aprocedure analogous to that described in connection with 9 (Example 9)except 1D (Example 1) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewere used as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46(s, 6H) 3.90 (s, 3H) 7.66 (d, J=8.08 Hz, 2H) 7.78 (d, J=8.59 Hz, 1H)8.04-8.14 (m, 4H) 8.38 (s, 1H) 12.89 (br. s., 1H); ESI-MS: m/z 394.0(M+H)⁻.

Example 20 Preparation of methyl4-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-ylcarbamoyl)benzoate(20)

The titled compound (yield=17%, yellow solid) was prepared using aprocedure analogous to that described in connection with 9 (Example 9)except 1C (Example 3) and3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewere used as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.58(s, 3H) 3.91 (s, 3H) 6.56 (br. s., 1H) 7.76 (d, J=8.59 Hz, 1H) 8.12 (d,J=8.59 Hz, 4H) 8.25 (d, J=8.59 Hz, 2H) 13.15 (br. s., 1H); ESI-MS: m/z394.0 (M+H)⁺.

Example 21 Preparation of4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(21)

The titled compound (yield=20%, white solid) was prepared using aprocedure analogous to that described in connection with 9 (Example 9)except 2F (Example 2) and3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewere used as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27(s, 6H) 2.59 (br. s., 3H) 3.49 (br. s., 2H) 7.57 (d, J=8.34 Hz, 2H) 7.74(d, J=8.59 Hz, 1H) 8.02 (br. s., 1H) 8.05-8.13 (m, 3H) 12.86 (s, 1H);ESI-MS: m/z 408.0 (M+H)⁺.

Example 22 Preparation ofN-(5-(2-ethyl-1H-imidazol-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(22)

The titled compound (yield=31%) was prepared using a procedure analogousto that described in connection with 7 (Example 7) except2-ethyl-1H-imidazole was used as a starting material. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.28 (t, J=7.58 Hz, 3H) 1.47 (s, 6H) 3.12 (q, J=7.41 Hz,2H) 7.68 (d, J=8.34 Hz, 2H) 7.84 (s, 1H) 7.91 (d, J=8.59 Hz, 1H)8.08-8.19 (m, 3H) 8.51 (d, J=8.59 Hz, 1H) 13.24 (br. s., 1H); ESI-MS:m/z 408.0 (M+H)⁺.

Example 23 Preparation of methyl4-(5-(3-ethyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-ylcarbamoyl)benzoate(23)

The titled compound (yield=30%) was prepared using a procedure analogousto that described in connection with 7 (Example7) except2-ethyl-1H-imidazole and 1C (Example 1) were used as starting materials.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (t, J=7.33 Hz, 3H) 3.09 (q, J=7.16Hz, 2H) 3.92 (s, 3H) 7.73 (br. s., 1H) 7.89 (d, J=8.59 Hz, 1H) 8.07 (br.s., 1H) 8.15 (d, J=8.08 Hz, 2H) 8.27 (d, J=8.34 Hz, 2H) 8.52 (d, J=8.34Hz, 1H); ESI-MS: m/z 408.0 (M+H)⁺.

Example 24 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(24)

The titled compound (yield=7%) was prepared using a procedure analogousto that described in connection with 10 (Example 10) except3-(trifluoromethyl)-1H-pyrazol-4-ylboronic acid and 1D (Example 1) wereused as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47 (s, 6H)7.67 (d, J=8.34 Hz, 2H) 7.76 (d, J=8.34 Hz, 1H) 8.11 (d, J=8.34 Hz, 2H)8.20 (d, J=8.59 Hz, 1H) 8.57 (s, 1H) 12.97 (s, 1H) 13.88 (br. s., 1H);ESI-MS: m/z 448.0 (M+H)⁻.

Example 25 Preparation of4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(25)

Intermediate 9A(N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzamide)was prepared using a procedure analogous to that described in connectionwith 9 (Example 9) except4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzoic acid and 1B(Example 1) were used as starting materials.

The titled compound 25 (yield=2 %) was prepared using a procedureanalogous to that described in connection with 9 (Example 9) except 9Aand 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewere used as starting materials. 25: ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.60 (s, 3H) 7.75 (s, 1H) 7.89 (d, J=8.34 Hz, 2H) 8.01 (br. s., 1H) 8.11(s, 1H) 8.26 (d, J=8.59 Hz, 2H) 9.04 (s, 1H) 13.08 (s, 1 H); ESI-MS: m/z502.0 (M+H)⁺.

Example 26 Preparation of4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(3-methylpyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(26)

The titled compound (yield=70%) was prepared using a procedure analogousto that described in connection with 9 (Example 9) except 2F (Example 2)and 3-methylpyridin-4-ylboronic acid were used as starting materials. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.21 (s, 6H) 2.47 (s, 3H) 3.42 (s, 2H) 7.52(d, J=8.59 Hz, 2H) 7.81-7.90 (m, 2H) 8.04 (d, J=8.59 Hz, 2H) 8.26 (d,J=8.34 Hz, 1H) 8.69 (d, J=4.29 Hz, 1H) 8.75 (br. s., 1H) 13.05 (br. s.,1H); ESI-MS: m/z 419.0 (M+H)⁻.

Example 27 Preparation of4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(4-(methylcarbamoyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)benzamide(27)

The titled compound (yield=15%, white solid) was prepared using aprocedure analogous to that described in connection with 9 (Example 9)except 4-(methylcarbamoyl)phenylboronic acid and 2F (Example 2) wereused as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (s, 6H)2.82 (d, J=4.55 Hz, 3H) 3.49 (d, J=5.31 Hz, 2H) 4.75-4.81 (m, 1H) 7.58(d, J=8.84 Hz, 2H) 7.98 (d, J=8.59 Hz, 2H) 8.11 (d, J=8.84 Hz, 2H)8.17-8.22 (m, 1H) 8.22-8.28 (m, 3H) 8.56 (q, J=4.63 Hz, 1H) 13.02 (s,1H); ESI-MS: m/z 461.0 (M+H)⁺.

Example 28 Preparation of4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(2-methoxypyrimidin-5-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(28)

The titled compound (yield=33%, white solid) was prepared using aprocedure analogous to that described in connection with 9 (Example 9)except 2F (Example 2) and 2-methoxypyrimidin-5-yl boronic acid were usedas starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (s, 6H) 3.49(d, J=5.05 Hz, 2H) 4.01 (s, 3H) 4.78 (t, J=5.31 Hz, 1H) 7.58 (d, J=8.59Hz, 2H) 8.10 (d, J=8.59 Hz, 2H) 8.16 (d, J=8.59 Hz, 1H) 8.22-8.29 (m,1H) 9.33 (s, 2H) 13.02 (s, 1H); ESI-MS: m/z 436.0 (M+H)⁺.

Example 29 Preparation ofN-(5-(6-acetamidopyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide(29)

The titled compound (yield=14%, white solid) was prepared using aprocedure analogous to that described in connection with 10 (Example 10)exceptN-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamideand 2F (Example 2) were used as starting materials. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.27 (s, 6H) 2.14 (s, 3H) 3.49 (d, J=5.31 Hz, 2H) 4.78(t, J=5.31 Hz, 1H) 7.58 (d, J=8.59 Hz, 2H) 8.06-8.18 (m, 3H) 8.18-8.26(m, 2H) 8.52 (dd, J=8.84, 2.53 Hz, 1H) 9.09 (d, J=1.77 Hz, 1H) 10.73 (s,1H) 13.00 (s, 1H); ESI-MS: m/z 462.0 (M+H)⁺.

Example 30 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide (30)

The titled compound (yield=26%, white solid) was prepared using aprocedure analogous to that described in connection with 10 (Example 10)except that 1D (Example 1) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were used asstarting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47 (s, 6H) 7.68(d, J=8.34 Hz, 2H) 8.12 (d, J=8.34 Hz, 2H) 8.29-8.46 (m, 4H) 8.87 (br.s., 2H) 13.15 (br. s., 1H); ESI-MS: m/z 391.0 (M+H)⁺.

Example 31 Preparation ofN-(5-(2-fluoropyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide(31)

The titled compound (yield=38%, light yellow solid) was prepared using aprocedure analogous to that described in connection with 10 (Example 10)except that 2F (Example 2) and 2-fluoropyridin-4-ylboronic acid wereused as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (s, 6H)3.49 (d, J=3.03 Hz, 2H) 4.78 (br. s., 1H) 7.59 (d, J=8.59 Hz, 2H) 7.91(s, 1H) 8.06-8.16 (m, 3H) 8.27-8.36 (m, 2H) 8.38 (d, J=5.31 Hz, 1H)13.11 (s, 1H); ESI-MS: m/z 423.0 (M+H)⁻.

Example 32 Preparation ofN-(5-(6-aminopyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide(32)

The titled compound (yield=22%, white solid) was prepared using aprocedure analogous to that described in connection with 10 (Example 10)except that 2F (Example 2) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine were usedas starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (s, 6H) 3.17(s, 2H) 3.49 (s, 1H) 7.03 (d, J=9.35 Hz, 1H) 7.58 (d, J=8.59 Hz, 2H)7.89 (br. s., 2H) 8.08 (dd, J=11.12, 8.59 Hz, 3H) 8.24 (d, J=8.59 Hz,1H) 8.62 (dd, J=9.35, 2.27 Hz, 1H) 8.72 (d, J=1.77 Hz, 1H) 13.02 (s,1H); ESI-MS: m/z 420.0 (M+H)⁻.

Example 33 Preparation of4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(6-hydroxypyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(33)

The titled compound (yield=21%, tan solid) was prepared using aprocedure analogous to that described in connection with 10 (Example 10)except 2F (Example 2) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol were used asstarting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (s, 6H) 3.48(s, 2H) 6.48 (d, J=9.60 Hz, 1H) 7.58 (d, J=8.84 Hz, 2H) 7.96 (d, J=8.59Hz, 1H) 8.09 (d, J=8.59 Hz, 2H) 8.14 (d, J=8.59 Hz, 1H) 8.20 (d, J=2.27Hz, 1H) 8.27 (dd, J=9.60, 2.78 Hz, 1H) 11.99 (br. s., 1H) 12.93 (br. s.,1H); ESI-MS: m/z 421.0 (M+H)⁻.

Example 34 Preparation of4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(34)

The titled compound (yield=63%, white solid) was prepared using aprocedure analogous to that described in connection with 10 (Example 10)except 2F (Example 2) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were used asstarting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (s, 6H) 3.49(s, 2H) 7.59 (d, J=8.59 Hz, 2H) 8.10-8.12 (d, J=8.59 Hz, 2H) 8.31-8.36(m, 1H) 8.37-8.44 (m, 3H) 8.85 (d, J=5.31 Hz, 2H) 13.15 (s, 1H); ESI-MS:m/z 405.0 (M+H)⁺.

Example 35 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(6-hydroxypyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(35)

The titled compound (yield=22%, tan solid) was prepared using aprocedure analogous to that described in connection with 10 (Example 10)except 2F (Example 2) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol were used asstarting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47 (s, 6H) 5.23(s, 1H) 6.48 (d, J=9.60 Hz, 1H) 7.63-7.70 (m, 2H) 7.96 (d, J=8.84 Hz,1H) 8.07-8.16 (m, 3H) 8.21 (d, J=2.53 Hz, 1H) 8.27 (dd, J=9.60, 2.78 Hz,1H) 12.00 (br. s., 1H) 12.94 (br. s., 1H); ESI-MS: m/z 407.0 (M+H)⁺.

Example 36 Preparation of(R)-4-(2-hydroxypropan-2-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(36)

The titled compound (yield=49%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except that (R)-pyrrolidin-3-ol was used as a starting material. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.46 (s, 6H) 1.86-1.99 (m, 1H) 2.00-2.12 (m,1H) 3.38 (d, J=11.12 Hz, 1H) 3.48-3.59 (m, 3H) 4.38-4.46 (m, 1H) 6.61(d, J=8.84 Hz, 1H) 7.63 (d, J=8.59 Hz, 2H) 7.87 (d, J=9.09 Hz, 1H) 8.06(d, J=8.84; Hz, 2H) 12.54 (br. s., 1H); ESI-MS: m/z 399.0 (M+H)⁺.

Example 37 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-morpholinothiazolo[5,4-b]pyridin-2-yl)benzamide(37)

The titled compound (yield=12%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except morpholine was used a starting material. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.46 (s, 6H) 3.46-3.55 (m, 4H) 3.68-3.78 (m, 4H) 7.02 (d,J=9.09 Hz, 1H) 7.64 (d, J=8.59 Hz, 2H) 7.93 (d, J=9.09 Hz, 1H) 8.06 (d,J=8.59 Hz, 2H) 12.63 (s, 1H); ESI-MS: m/z 399.0 (M+H)⁺.

Example 38 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(piperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide (38)

The titled compound (yield=13%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except piperidine was used as a starting material. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.46 (s, 6H) 1.59 (br. s., 6H) 3.45-3.62 (m, 4H) 6.99 (d,J=9.09 Hz, 1H) 7.63 (d, J=8.59 Hz, 2H) 7.86 (d, J=9.09 Hz, 1H) 8.06 (d,J=8.59 Hz, 2H) 12.56 (s, 1H); ESI-MS: m/z 397.0 (M+H)⁺.

Example 39 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(3-oxopiperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(39)

The titled compound (yield=15%, tan color solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except piperazin-2-one was used as a starting material, and the reactionwas heated at 200° C. for 2 h. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46 (s,6H) 3.33 (br. s., 2H) 3.79 (t, J=5.31 Hz, 2H) 4.06 (s, 2H) 7.00 (d,J=9.09 Hz, 1H) 7.64 (d, J=8.34 Hz, 2H) 7.94 (d, J=8.84 Hz, 1H) 8.06 (d,J=8.34 Hz, 2H) 8.14 (br. s., 1H) 12.63 (s, 1H); ESI-MS: m/z 412.0(M+H)⁺.

Example 40 Preparation ofN-(5-(2-chloropyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(40)

The titled compound (yield=43%, yellow solid) was prepared using aprocedure analogous to that described in connection with 9 (Example 9)except 1D (Example 1) and2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine wereused as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47 (s, 6H)5.24 (s, 1H) 7.67 (d, J=8.34 Hz, 2H) 8.12 (d, J=8.34 Hz, 2H) 8.18 (d,J=5.56 Hz, 1H) 8.25 (s, 1H) 8.28-8.37 (m, 2H) 8.55 (d, J=5.31 Hz, 1H)13.12 (s, 1H); ESI-MS: m/z 425.0 (M+H)⁺.

Example 41 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(2-methoxypyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(41)

The titled compound (yield=37%, yellow solid) was prepared using aprocedure analogous to that described in connection with 9 (Example 9)except 1D (Example 1) and 2-methoxypyridin-4-ylboronic acid were used asstarting materials. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47 (s, 6H) 3.93(s, 3H) 7.54 (s, 1H) 7.67 (d, J=8.59 Hz, 2H) 7.75 (dd, J=5.43, 1.39 Hz,1H) 8.11 (d, J=8.59 Hz, 2H) 8.25 (d, J=1.52 Hz, 2H) 8.31 (d, J=5.31 Hz,1H) 13.07 (br. s., 1H); ESI-MS: m/z 421.0 (M+H)⁺.

Example 42 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(piperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(42)

The titled compound (yield=25%, white solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except piperazine was used as a starting material, and the reaction washeated at 200° C. for 20 min. ¹H NMR (400 MHz, MeOD) δ ppm 1.57 (s, 6H)3.33-3.40 (m, 4H) 3.82-3.91 (m, 4H) 7.07 (d, J=9.09 Hz, 1H) 7.69 (d,J=8.84 Hz, 2H) 7.95 (d, J=9.09 Hz, 1H) 8.01 (d, J=8.84 Hz, 2H); ESI-MS:m/z 398.0 (M+H)⁺.

Example 43 Preparation ofN-(5-(4-(hydroxymethyl)piperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(43)

The titled compound (yield=22%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except piperidin-4-ylmethanol was used as a starting material. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.09-1.35 (m, 2H) 1.46 (s, 6H) 1.63 (br. s.,1H) 1.71-1.81 (m, 2H) 2.77-2.94 (m, 2H) 3.28 (d, J=6.32 Hz, 2H)4.26-4.45 (m, 2H) 7.00 (d, J=9.09 Hz, 1H) 7.64 (d, J=8.34 Hz, 2H) 7.86(d, J=8.84 Hz, 1H) 8.06 (d, J=8.34 Hz, 2H) 12.57 (br. s., 1H); ESI-MS:m/z 427.0 (M+H)⁺.

Example 44 Preparation ofN-(5-(6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(44)

The titled compound (yield=7%, white solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine hydrochloride andEt₃N (6.0 equivalents) were used, and the reaction was first heated at180° C. for 20 min and then 200° C. for 20 min. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.46 (s, 6H) 2.78 (br. s., 2H) 3.95 (t, J=5.43 Hz, 2H)4.62 (s, 2H) 7.09 (d, J=0.09 Hz, 1H) 7.50 (br. s., 1H) 7.64 (d, 2H) 7.91(d, J=8.84 Hz, 1H) 8.06 (d, 2H) 12.59 (br. s., 1H); ESI-MS: m/z 435.0(M+H)⁺.

Example 45 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(5-oxo-1,4-diazepan-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(45)

The titled compound (yield=7%, tan color solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except 1,4-diazepan-5-one was used as a starting material, and thereaction was first heated at 180° C. for 20 min and then 200° C. for 20min. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46 (s, 6H) 2.52-2.59 (m, 2H) 3.23(br. s., 2H) 3.82 (t, J=6.19 Hz, 4H) 6.99 (d, J=9.09 Hz, 1H) 7.64 (d,J=8.34 Hz, 2H) 7.91 (d, J=8.84 Hz, 1H) 8.06 (d, J=8.59 Hz, 2H) 12.59 (s,1H); ESI-MS: m/z 426.0 (M+H)⁺.

Example 46 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(4-methoxypiperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(46)

The titled compound (yield=37%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except 4-methoxypiperidine was used as a starting material, and thereaction was heated at 200° C. for 20 min. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.46 (s, 6H) 1.93 (br. s., 2H) 3.13-3.26 (m, 2H) 3.29 (s, 3H) 3.43(br. s., 2H) 3.98 (d, J=13.39 Hz, 2H) 4.10 (br. s., 1H) 5.21 (br. s.,1H) 7.02 (d, J=9.09 Hz, 1H) 7.64 (d, J=8.34 Hz, 2H) 7.88 (d, J=9.09 Hz,1H) 8.06 (d, J=8.34 Hz, 2H) 12.58 (s, 1H); ESI-MS: m/z 427.0 (M+H)⁻.

Example 47 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(4-methylpiperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(47)

The titled compound (yield=39%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except 1-methylpiperazine was used as a starting material, and thereaction was heated at 200° C. for 20 min. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.46 (s, 6H) 2.87 (d, J=4.04 Hz, 3H) 3.06-3.27 (m, 4H) 3.54 (d,J=11.12 Hz, 2H) 4.46 (d, J=12.13 Hz, 2H) 7.13 (d, J=9.09 Hz, 1H) 7.64(d, J=8.59 Hz, 2H) 8.01 (d, J=8.84 Hz, 1H) 8.06 (d, J=8.59 Hz, 2H) 9.77(br. s., 1H) 12.69 (s, 1H); ESI-MS: m/z 412.0 (M+H)⁻.

Example 48 Preparation of(S)-4-(2-hydroxypropan-2-yl)-N-(5-(2-(methoxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(48)

The titled compound (yield=33%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except (S)-2-(methoxymethyl)pyrrolidine was used as a starting material,and the reaction was heated at 200° C. for 20 min.¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.46 (s, 6H) 1.92-1.99 (m, 2H) 2.00-2.09 (m, 1H)3.24-3.36 (m, 5H) 3.48-3.58 (m, 2H) 4.22 (br. s., 2H) 6.68 (d, J=9.09Hz, 1H) 7.63 (d, J=8.84 Hz, 2H) 7.87 (d, J=9.09 Hz, 1H) 8.06 (d, J=8.59Hz, 2H) 12.54 (br. s., 1H); ESI-MS: m/z 427.0 (M+H)⁺.

Example 49 Preparation ofN-(5-(4-acetylpiperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(49)

The titled compound (yield=4%, white solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except 1-(piperazin-1-yl)ethanone was used as a starting material, andthe reaction was heated at 200° C. for 20 min. ¹H NMR (400 MHz, MeOD) δppm 1.57 (s, 6H) 2.16 (s, 3H) 3.58-3.64 (m, 2H) 3.70 (s, 4H) 3.71-3.76(m, 2H) 6.98 (d, J=9.09 Hz, 1H) 7.69 (d, J=8.84 Hz, 2H) 7.89 (d, J=9.09Hz, 1H) 8.00 (d, J=8.59 Hz, 2H); ESI-MS: m/z 440.0 (M+H)⁺.

Example 50 Preparation of(R)-4-(2-hydroxypropan-2-yl)-N-(5-(2-(methoxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(50)

The titled compound (yield=33%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except (R)-2-(methoxymethyl)pyrrolidine was used as a starting material,and the reaction was heated at 200° C. for 20 min. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.46 (s, 6H) 1.96 (d, J=5.56 Hz, 3H) 2.00-2.10 (m, 1H)3.24-3.37 (m, 5H) 3.53 (dd, J=9.35, 4.04 Hz, 2H) 4.22 (br. s., 1H) 6.68(d, J=9.09 Hz, 1H) 7.64 (d, J=8.34 Hz, 2H) 7.87 (d, J=8.84 Hz, 1H) 8.06(d, J=8.34 Hz, 2H) 12.55 (br. s., 1H); ESI-MS: m/z 427.0 (M+H)⁺.

Example 51 Preparation ofN-(5-(3-cyanopiperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(51)

The titled compound (yield=8%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except piperidine-3-carbonitrile was used as a starting material, andthe reaction was heated at 200° C. for 20 min. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.46 (s, 6H) 1.55-1.79 (m, 2H) 1.83-2.03 (m, 2H) 3.05-3.16 (m, 1H)3.47-3.59 (m, 1H) 3.60-3.72 (m, 1H) 3.78-3.84 (m, 1H) 3.87-3.94 (m, 1H)7.10 (d, J=9.35 Hz, 1H) 7.64 (d, J=8.59 Hz, 2H) 7.92 (d, J=9.09 Hz, 1H)8.06 (d, J=8.84 Hz, 2H) 12.63 (s, 1H); ESI-MS: m/z 422.0 (M+H)⁺.

Example 52 Preparation ofN-(5-(4-hydroxypiperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(52)

The titled compound (yield=45%, off-white solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except piperidin-4-ol was used as a starting material, and the reactionwas heated at 200° C. for 20 min. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.35-1.49 (m, 8H) 1.78-1.87 (m, 2H) 3.09-3.20 (m, 2H) 3.72 (ddd, J=8.53,4.55, 4.36 Hz, 1H) 4.04 (ddd, J=13.01, 4.29, 4.17 Hz, 2H) 5.21 (br. s.,1H) 7.01 (d, J=9.09 Hz, 1H) 7.64 (d, J=8.59 Hz, 2H) 7.87 (d, J=9.09 Hz,1H) 8.06 (d, J=8.59 Hz, 2H) 12.58 (s, 1H); ESI-MS: m/z 413.0 (M+H)⁻.

Example 53 Preparation of(S)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-2-carboxamide(53)

The titled compound (yield=27%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except (S)-pyrrolidine-2-carboxamide was used as a starting material,and the reaction was heated at 200° C. for 20 min. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.39 (s, 6H) 1.87-1.99 (m, 3H) 2.07-2.19 (m, 1H)3.36-3.38 (m, 1H) 3.57-3.66 (m, 1H) 4.19-4.27 (m, 1H) 6.49 (d, J=9.09Hz, 1H) 6.93 (s, 1H) 7.35 (s, 1H) 7.56 (d, J=8.84 Hz, 2H) 7.82 (d,J=8.84 Hz, 1H) 7.99 (d, J=8.59 Hz, 2H) 12.47 (s, 1H); ESI-MS: m/z 426.0(M+H)⁺.

Example 54 Preparation of(R)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-2-carboxamide(54)

The titled compound (yield=12%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except (R)-pyrrolidine-2-carboxamide was used as a starting material,and the reaction was heated at 200° C. for 20 min. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.39 (s, 6H) 1.91 (br. s., 3H) 2.08-2.20 (m, 1H) 3.61(br. s., 2H) 4.24 (d, J=8.08 Hz, 1H) 6.49 (d, J=8.84 Hz, 2H) 6.93 (br.s., 1H) 7.35 (br. s., 1H) 7.56 (d, J=8.34 Hz, 2H) 7.82 (d, J=8.84 Hz,1H) 7.99 (d, J=8.59 Hz, 2H) 12.47 (s, 1H); ESI-MS: m/z 426.0 (M+H)⁻.

Example 55 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(4-oxo-3,4,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(5H)-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(55)

The titled compound (yield=7%, orange solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one hydrochlorideand Et₃N (6.0 equivalents) were used, and the reaction was first heatedat 180° C. for 1 h. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47 (s, 6H) 2.76(t, J=5.18 Hz, 2H) 3.90 (t, J=5.68 Hz, 2H) 4.37 (s, 2H) 7.12 (d, J=9.09Hz, 1H) 7.65 (d, J=8.34 Hz, 2H) 7.96 (d, J=9.09 Hz, 1H) 8.03-8.13 (m,3H) 12.64 (s, 1H); ESI-MS: m/z 463.0 (M+H)⁻.

Example 56 Preparation of(S)-N-(5-(2-(hydroxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(56)

The titled compound (yield=38%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except (S)-pyrrolidin-2-ylmethanol was used, and the reaction was heatedat 200° C. for 20 min. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39 (s, 6H)1.82-1.91 (m, 2H) 1.93-2.01 (m, 2H) 3.17-3.29 (m, 2H) 3.42-3.50 (m, 1H)3.54 (dd, J=10.61, 3.79 Hz, 1H) 3.99 (br. s., 1H) 6.61 (d, J=8.84 Hz,1H) 7.56 (d, J=8.59 Hz, 2H) 7.80 (d, J=8.84 Hz, 1H) 7.99 (d, J=8.59 Hz,2H) 12.47 (br. s., 1H); ESI-MS: m/z 413.0 (M+H)⁻.

Example 57 Preparation of(S)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-3-carboxylicacid (57)

The titled compound (yield=21%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except (S)-pyrrolidine-3-carboxylic acid hydrochloride and Et₃N (6.0equivalents) were used, and the reaction was heated at 180° C. for 40min. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46 (s, 6H) 2.12-2.30 (m, 2H) 3.22(ddd, J=13.77, 7.07, 6.95 Hz, 1H) 3.45-3.58 (m, 2H) 3.60-3.75 (m, 2H)5.21 (s, 1H) 6.64 (d, J=8.84 Hz, 1H) 7.64 (d, J=8.59 Hz, 2H) 7.88 (d,J=8.84 Hz, 1H) 8.06 (d, J=8.59 Hz, 2H) 12.55 (br. s., 2H); ESI-MS: m/z427.0 (M+H)⁺.

Example 58 Preparation of(R)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-3-carboxylicacid (58)

The titled compound (yield=12%, yellow solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except (R)-pyrrolidine-3-carboxylic acid hydrochloride and Et₃N (6.0equivalents) were used, and the reaction was heated at 180° C. for 40min. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46 (s, 6H) 2.14-2.29 (m, 2H)3.16-3.27 (m, 1H) 3.43-3.73 (m, 4H) 6.63 (d, J=8.84 Hz, 1H) 7.63 (d,J=8.34 Hz, 2H) 7.87 (d, J=8.84 Hz, 1H) 8.05 (d, J=8.34 Hz, 2H) 12.54(br. s., 1H); m/z 427.0 (M+H)⁺.

Example 59 Preparation ofN-(5-(3-(hydroxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide(59)

The titled compound (yield=12%, yellow oil) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except pyrrolidin-3-ylmethanol was used as a starting material, and thereaction was heated at 200° C. for 20 min. ¹H NMR (400 MHz, MEOD) δ ppm1.57 (s, 6H) 1.87-1.99 (m, 1H) 2.16-2.28 (m, 1H) 2.55-2.69 (m, 1H)3.33-3.43 (m, 3H) 3.54-3.64 (m, 1H) 3.64-3.77 (m, 2H) 6.83 (d, J=9.3 Hz,1H) 7.69 (d, J=8.34 Hz, 2H) 7.97-8.07 (m, 3H); ESI-MS: m/z 413.0 (M+H)⁺.

Example 60 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(4-(methylsulfonyl)piperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide(60)

The titled compound (yield=12%, white solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8))except 1-(methylsulfonyl)piperazine hydrochloride and Et₃N (6.0equivalents) were used, and the reaction was heated at 180° C. for 80min. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46 (s, 6H) 2.92 (s, 3H) 3.20-3.27(m, 4H) 3.65-3.74 (m, 4H) 5.21 (br. s., 1H) 7.08 (d, J=9.09 Hz, 1H) 7.64(d, J=8.34 Hz, 2H) 7.95 (d, J=8.84 Hz, 1H) 8.06 (d, J=8.34 Hz, 2H) 12.64(s, 1); ESI-MS: m/z 476.0 (M+H)⁻.

Example 61 Preparation of4-(2-hydroxypropan-2-yl)-N-(5-(1,1-dioxothiomorpholino)thiazolo[5,4-b]pyridin-2-yl)benzamide(61)

The titled compound (yield=2%, white solid) was prepared using aprocedure analogous to that described in connection with 8 (Example 8)except thiomorpholine 1,1-dioxide was used as a starting material, andthe reaction was heated at 200° C. for 50 min. ¹H NMR (400 MHz, MeOD) δppm 1.57 (s, 6H) 3.10-3.18 (m, 4H) 4.23 (br. s., 4H) 7.11 (d, J=8.84 Hz,1H) 7.69 (d, J=8.34 Hz, 2H) 7.94 (d, J=9.09 Hz, 1H) 8.01 (d, J=8.34 Hz,2H); ESI-MS: m/z 447.0 (M+H)⁺.

Example A Preparation of ASK1 Protein

Cloning of cDNA encoding human ASK1 was conducted by PCR using primers,5′-AAAAGTCGACATGGACTACAAGGACGACGATGACAAGGTGAACAC CATTACCGAAGAGAAGGGGA-3(SEQ ID NO: 1) and 5′-AAAGCGGCCGCTCAA GTCTGTTTGTTTCGAAAGTCAATG-3′ (SEQID NO: 2), from human heart cDNA library (Becton, Dickinson andCompany). The PCR product was subjected to agarose gel (1%)electrophoresis, a 2.2 kb DNA fragment containing an ASK1 gene wasrecovered from the gel, and then digested with restriction enzymes, NotIand SalI, and inserted into a plasmid pFASTBAC1 (Invitrogen) to preparea plasmid pFB-ASK1. The insert was verified by sequencing. Recombinantbaculovirus was prepared according to the procedure of the Bac-to-Bacbaculovirus expression system (Invitrogen).

Sf-21 cells were seeded to achieve 1×10⁶ cells/mL in 100 mL of Sf-900 IISFM medium (Invitrogen) which contains 10% fetal calf serum and thencultured at 27° C. for 24 hrs. To express ASK1 in cells, 0.15 mL of therecombinant baculovirus virus stock was added to cells, and the thencultured for 60 hrs. The cells were separated from the culture solutionby centrifugation at 3000 rpm for 10 min and washed once with PBS. Thecells were suspended in 10 mL of lysis buffer (25 mM HEPES (pH 7.5), 1%Triton X, 130 mM NaCl, 1 mM EDTA, 1 mM DTT, 25 mM β-glycerophosphate,Protease inhibitor complete (Roche), 1 mM sodium orthovanadate) andruptured by four times of treatment with a homogenizer (POLYTRON) at20000 rpm for 30 seconds. Active ASK1 protein was purified from asupernatant obtained by centrifugal separation at 40000 rpm for 45 minusing anti-FLAG M2 Affinity Gel (Sigma).

Example B Scintillation Assay for Measuring the Inhibitory Effect ofExemplified Compounds of the Invention Against ASK1

The test compounds (2.5 μL) dissolved in DMSO were added to wellscontaining 37.5 μl of the reaction solution (25 mM HEPES (pH 7.5), 10 mMmagnesium acetate, 1 mM DTT) including 30 ng of active ASK1 protein and1 μg of myelin basic protein (Wako), and incubated at room temperaturefor 5 min. To start the reaction, 10 μL of ATP solution (2.5 μM ATP, 0.1μCi [γ-³²P]ATP) was added to wells. After incubating at room temperaturefor 30 min, the reaction was terminated by adding 50 μl of 20% TCAsolution. The reaction solution was incubated at 4° C. for 30 min and anacid-insoluble fraction was transferred onto a GF/C filter (Packard)with Cell Harvester (Packard), and washed with 250 mM phosphoric acid.After drying at 45° C. for 60 min., 40 μL of Microscint 0 (Packard) wasadded and the radioactivity was measured with TopCount (Packard). Theconcentrations (IC₅₀ value) of the test compounds necessary for 50%inhibition of kinase activity were calculated by PRISM 3.0 (GraphpadSoftware).

Example C Homogeneous Time-Resolved Fluorescence (HTRF) Assay forMeasuring the Inhibitory Effect of Exemplified Compounds of theInvention Against ASK1

Recombinant human ASK1 is purchased from Millipore (Cat #14-606). Theenzymatic assay of ASK1 is set up by using HTRF® KinEASE™ STK S3 kit,the Universal Assay for Serine/Threonine Kinases kit from CisBio.

The inhibitory properties of compounds to ASK1 may be determined using awhite 384-well-plate format under the following reaction conditions: 25nM ASK1, 1 μM CisBio STK S3-biotion peptide, 100 μM ATP, and 1% -2% DMSOin kinase assay buffer of 50 mM HEPES, pH 7.3, 10 mM NaCl, 10 mM MgCl₂,0.01% Brij35, 0.2 mM EDTA, and 1 mM DTT. Reaction product is determinedquantitatively by HTRF after the addition of detection reagent SA-XL665and STK-antibody-cryptate.

The assay reaction may be initiated as follows: 2 μl of the mixture of 3μM CisBio STK S3-biotion peptide and 300 μM ATP with 2 μl of testcompound (2 fold serial dilutions for 11 data points for each inhibitor)containing 3%-6% DMSO are added to each well of the plate, followed bythe addition of 2 μL of 75 nM ASK1 to initiate the reaction (finalenzyme concentration was 25 nM for ASK1). The reaction mixture may thenbe incubated at room temperature for 1 hour, and quenched and developedby the addition of 6 μL of 100-fold diluted STK-antibody-Cryptate and250 nM SA-XL665 in Cisbio HTRF detection buffer (50 mM HEPES, pH7.0,0.1% BSA, 0.8 M KF, and 20 mM EDTA). The fluorescence intensity ismeasured at 620 nm (Cryptate) and 665 nm (XL665) after a 1-2 hourincubation at room temperature. A ratio is calculated (665/620) for eachwell and is fitted to the standard IC₅₀ curve to determine inhibitionconstants (IC₅₀).

Example D In Vitro IC50 Values of Compounds of the Invention AgainstASK1

The enzyme activities of the compounds of the present invention againstASK1 were determined using the assay disclosed in Example A and B. Theresulted IC₅₀ values are reported in Table 1.

TABLE 1 IC₅₀ of Exemplified Compounds Against ASK1 Enzyme ActivityCompound No IC₅₀(nM) 5 >1,000   7 100-1,000 8 >1,000   9 <100 10100-1,000 11 100-1,000 12 <100 13 <100 14 100-1,000 15 <100 19 100-1,00020 >1,000   21 <100 22 >1,000   26 100-1,000 30 100-1,000 33 <100 34100-1,000 35 <100 36 >1,000   38 >1,000  

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein N^(a) denotes anitrogen atom; ring A is selected from the group consisting of(C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl, (C₇₋₁₂)bicycloalicyclyl,hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₁)aryl,(C₇₋₁₂)bicycloaryl, and hetero(C₁₋₁₁)bicycloaryl, each unsubstituted orsubstituted with 1-5 substituents independently selected from the groupconsisting of hydroxyl, oxo, halo, cyano, (C₁₋₆)alkyl, (C₁₋₆)alkenyl,(C₁₋₆)alkynyl, halo(C₁₋₆)alkyl, (C₁₋₆)alkylcarbonylamino,(C₁₋₆)alkylaminocarbonyl, (C₁₋₆)alkoxy, amino, hydroxy(C₁₋₆)alkyl,(C₁₋₆)alkoxy(C₁₋₆)alkyl, (C₁₋₆)alkylcarbonyl, aminocarbonyl,hydroxylcarbonyl, and (C₁₋₆)alkylsulfonyl, each unsubstituted orsubstituted; X is selected from the group consisting of CR₃ and N; R₁ isa —C(O)-ring B; where ring B is selected from the group consisting of(C₄₋₁₂)alicyclyl, hetero(C₃₋₁₁)alicyclyl, (C₈₋₁₂)bicycloalicyclyl,hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted with 1-3 substituents independently selected from the groupconsisting of halo, nitro, cyano, thio, mercapto, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, amido, carboxamido,carbamoyl, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,sulfamoyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each unsubstituted or substituted; R₂ is selected from the groupconsisting of hydrogen, (C₁₋₆)alkoxy, carbonyl, oxycarbonyl,aminocarbonyl, sulfonyl, (C₁₋₆)alkyl, (C₁₋₆)alkenyl, (C₁₋₆)alkynyl,hetero(C₁₋₆)alkyl, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,carbonyl(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl(C₁₋₃)alkyl,hetero(C₁₋₅)cycloalkyl(C₁₋₃)alkyl, (C₃₋₆)alicyclyl,hetero(C₁₋₅)alicyclyl, each substituted or unsubstituted; and R₃ isselected from the group consisting of hydrogen, halo, nitro, cyano,thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,carbonylamino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl,(C₈₋₁₂)bicycloalicyclyl, hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,each substituted or unsubstituted.
 2. The compound according to claim 1,wherein ring B is selected from the group consisting of(C₄₋₁₂)alicyclyl, hetero(C₃₋₁₂)alicyclyl, (C₈₋₁₂)bicycloalicyclyl,hetero(C₃₋₁₁)bicycloalicyclyl, (C₄₋₆)aryl, hetero(C₁₋₆)aryl,(C₈₋₁₀)bicycloaryl, and hetero(C₁₋₁₀)bicycloaryl, each unsubstituted orsubstituted with said 1-3 substituents of ring B.
 3. The compoundaccording to claim 2, wherein ring B is a five-membered heteroarylcontaining up to four heteroatoms, where each of said four heteroatomsis independently selected from the group consisting of nitrogen, oxygenand sulfur, and where the heteroaryl is unsubstituted or substitutedwith said 1-3 substituents of ring B.
 4. The compound according to claim3, wherein ring B is selected from the group consisting of furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl, eachunsubstituted or substituted with said 1-3 substituents of ring B. 5.The compound according to claim 2, wherein ring B is a thienyl,unsubstituted or substituted with said 1-3 substituents of ring B. 6.The compound according to claim 1, wherein ring B is a six-membered arylor heteroaryl, where the heteroaryl contains up to four nitrogen atoms,and where the aryl or heteroaryl is unsubstituted or substituted withsaid 1-3 substituents of ring B.
 7. The compound according to claim 6,wherein ring B is selected from the group consisting of phenyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, eachunsubstituted or substituted with said 1-3 substituents of ring B. 8.The compound according to claim 6, wherein ring B is a phenyl, eachunsubstituted or substituted with said 1-3 substituents.
 9. The compoundaccording to claim 6, wherein ring B is a pyridinyl, each unsubstitutedor substituted with said 1-3 substituents of ring B.
 10. The compoundaccording to claim 1, wherein each of said 1-3 substituents of ring B isindependently selected from the group consisting of halo, nitro, oxy,hydroxy, (C₁₋₆)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,(C₁₋₆)alkyl, (C₁₋₆)alkenyl, (C₁₋₆)alkynyl, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aza(C₁₋₆)alkyl, oxa(C₁₋₆)alkyl, oxo(C₁₋₆)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₆)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₃₋₇)alicyclyl,hetero(C₃₋₇)alicyclyl, (C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, eachunsubstituted or substituted.
 11. The compound according to claim 1,wherein each of said 1-3 substituents of ring B is independentlyselected from the group consisting of halo, hydroxyl, nitro, thio,cyano, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, halo(C₁₋₆)alkyl,(C₁₋₆)alkoxy, hydroxyl(C₁₋₆)alkyl, mercapto, sulfinyl, sulfonyl,sulfamoyl, amino, amido, carboxyamido, carbamoyl, carbonyl andcarbonyloxy, each unsubstituted or substituted.
 12. The compoundaccording to claim 1, wherein each of said 1-3 substituents of ring B isindependently selected from the group consisting of hydroxyl, halo,cyano, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, halo(C₁₋₆)alkyl,—C(CH₃)(OH)CF₃, (C₁₋₆)alkoxy,

where k is 1, 2, 3, or 4; and R₂₁ is selected from the group consistingof hydroxyl, (C₁₋₄)alkyl, (C₂₋₄)alkenyl, (C₂₋₄)alkynyl, halo(C₁₋₄)alkyl,alkyloxy, —(CH₂)_(n)OH, —CF₃, —(CH₂)_(n)CN, —(CH₂)_(n)COOH,—(CH₂)_(n)CONH₂, —(CH₂)_(n)heteroaryl, and—(CH₂)_(n)O(CH₂)_(n)heteroaryl, where n is 0, 1, 2, 3, or
 4. 13. Thecompound according to claim 12, wherein R₂₁ is selected from the groupconsisting of methyl, perflurormethyl, hydroxyl, hydroxyl(C₁₋₄)alkyl,and cyano(C₁₋₄)alkyl.
 14. The compound according to claim 1, whereinring B is an unsubstituted or substituted phenyl consisting of theformula

where R₇, R₈, R₉, R₁₀, and R₁₁ are each independently selected from thegroup consisting of hydrogen, halo, hydroxyl, nitro, cyano, thio,(C₁₋₆)alkyl, halo(C₁₋₆)alkyl, (C₁₋₆)alkoxy, hydroxyl(C₁₋₆)alkyl,mercapto, sulfinyl, sulfonyl, sulfamoyl, amino, amido, carboxyamido,carbamoyl, carbonyl and carboxyl, each unsubstituted or substituted;provided that at least two of R₇, R₈, R₉, R₁₀, and R₁₁ are hydrogen. 15.The compound according to claim 14, wherein R₇, R₈, R₉, R₁₀, and R₁₁ areeach independently selected from the group consisting of hydrogen,hydroxyl, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, —C(CH₃)(OH)CF₃, (C₁₋₆)alkoxy,halo, cyano,

provided that at least two of R₇, R₈, R₉, R₁₀, and R₁₁ are hydrogen,where k is 1, 2, 3, or 4; and R₂₁ is selected from the group consistingof hydroxyl, (C₁₋₄)alkyl, halo(C₁₋₄)alkyl, alkyloxy, —(CH₂)_(n)OH, —CF₃,—(CH₂)_(n)CN, —(CH₂)_(n)COOH, —(CH₂)_(n)CONH₂, —(CH₂)_(n)heteroaryl, and—(CH₂)_(n)O(CH₂)_(n)heteroaryl, where n is 0, 1, 2, 3, or
 4. 16. Thecompound according to claim 15, wherein R₂₁ is selected from the groupconsisting of methyl, perfluoromethyl, hydroxyl, hydroxyl(C₁₋₄)alkyl,and cyano(C₁₋₄)alkyl.
 17. The compound according to claim 15, wherein R₉is independently selected from the group consisting of hydrogen,t-butyl, —C(CH₃)(OH)CF₃, —C(OH)(CH₃)₂, and —C(CH₂OH)(CH₃)₂; and R₇, R₈,R₁₀, and R₁₁ are each hydrogen.
 18. The compound according to claim 1,wherein ring B is selected from the group consisting of


19. The compound according to claim 1, wherein ring B is selected fromthe group consisting of


20. The compound according to claim 1, wherein ring A is selected fromthe group consisting of (C₅₋₇)alicyclyl, hetero(C₁₋₆)alicyclyl,(C₈₋₁₁)bicycloalicyclyl, hetero(C₄₋₁₀)bicycloalicyclyl, (C₆)aryl,hetero(C₁₋₅)aryl, (C₈₋₁₀)bicycloaryl, and hetero(C₄₋₁₀)bicycloaryl, eachunsubstituted or substituted with said 1-5 substituents of ring A, whereeach hetero(C₁₋₆)alicyclyl, hetero(C₄₋₁₀)bicycloalicyclyl,hetero(C₁₋₅)aryl, and hetero(C₄₋₁₀)bicycloaryl contains 1-4 heteroatomsindependently selected from the group consisting of nitrogen, oxygen andsulfur; and each (C₈₋₁₁)bicycloalicyclyl, hetero(C₄₋₁₀)bicycloalicyclyl,(C₈₋₁₀)bicycloaryl, and hetero(C₄₋₁₀)bicycloaryl comprises of a firstring fused to a second ring, where the first ring attaches directly tothe ring containing N^(a), and where the second ring is selected from agroup consisting of five, six and seven membered cyclyls.
 21. Thecompound according to claim 20, wherein ring A is selected from thegroup consisting of phenyl, hetero(C₂₋₅)aryl, (C₉₋₁₀)bicycloaryl, andhetero(C₅₋₁₀)bicycloaryl, each unsubstituted or substituted with said1-5 substituents of ring A, wherein the hetero(C₂₋₅)aryl is asix-membered heteroaryl; the (C₉₋₁₀)bicycloaryl comprises a first ringthat is a phenyl, and a second ring that is a five membered heteroarylor a phenyl; the hetero(C₅₋₁₀)bicycloaryl comprises a first ring that isa six-membered heteroaryl, and a second ring that is selected from thegroup consisting of phenyl, five-membered heteraryl and six-memberedheteraryl; each hetero(C₂₋₅)aryl and hetero(C₅₋₁₀)bicycloaryl contains1-4 heteroatoms each of which is independently selected from the groupconsisting of nitrogen, oxygen and sulfur.
 22. The compound according toclaim 21, wherein ring A is selected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.23. The compound according to claim 21, wherein ring A is selected fromthe group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.24. The compound according to claim 20, wherein ring A is selected fromthe group consisting of hetero(C₁₋₄)aryl and hetero(C₄₋₉)bicycloaryl,each unsubstituted or substituted with said 1-5 substituents, where thehetero(C₁₋₄)aryl is a five-membered heteroaryl; thehetero(C₄₋₉)bicycloaryl comprises of a first ring that is afive-membered heteroaryl, and a second ring that is selected from thegroup of phenyl, and five, six and seven membered heteroaryl; and eachhetero(C₁₋₄)aryl and hetero(C₄₋₉)bicycloaryl contains 1-4 heteroatomseach of which is independently selected from the group consisting ofnitrogen, oxygen and sulfur.
 25. The compound according to claim 24,wherein ring A is selected from the group

consisting of each unsubstituted or substituted with said 1-5substituents of ring A.
 26. The compound according to claim 24, whereinring A is selected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.27. The compound according to claim 20, wherein ring A is selected fromthe group consisting of (C₆)alicyclyl, hetero(C₁₋₅)alicyclyl,(C₉₋₁₁)bicycloalicyclyl, and hetero(C₅₋₁₀)bicycloalicyclyl, eachunsubstituted or substituted with said 1-5 substituents of ring A,wherein the hetero(C₁₋₅)alicyclyl is a six-membered heteroalicyclyl; the(C₉₋₁₁)bicycloalicyclyl comprises a first ring that is a six-memberedalicyclyl, and a second ring that is selected from the group consistingof five, six and seven membered cyclyl; thehetero(C₅₋₁₀)bicycloalicyclyl comprises a first ring that is asix-membered heteroalicyclyl, and a second ring that is a five, six orseven membered cyclyl; each hetero(C₁₋₅)alicyclyl andhetero(C₅₋₁₀)bicycloalicyclyl contains 1-4 heteroatoms, each of which isindependently selected from the group consisting of nitrogen, oxygen andsulfur.
 28. The compound according to claim 27, wherein ring A isselected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.29. The compound according to claim 20, wherein ring A is selected fromthe group consisting of (C₅)alicyclyl, hetero(C₁₋₄) alicyclyl,(C₈₋₁₀)bicycloalicyclyl, and hetero(C₄₋₉)bicycloalicyclyl, eachunsubstituted or substituted with said 1-5 substituents, wherein thehetero(C₁₋₄)alicyclyl is a five-membered heteroalicyclyl, the(C₈₋₁₀)bicycloalicyclyl comprises a first ring that is a five-memberedalicyclyl, and a second ring that is selected from the group consistingof five, six and seven membered cyclyl; the hetero(C₄₋₉)bicycloalicyclylcomprises a first ring that is a five-membered heterocycloalicyclyl, anda second ring that is selected from the group consisting of five, sixand seven membered cyclyl; and each hetero(C₁₋₄)alicyclyl andhetero(C₄₋₉)bicycloalicyclyl contains 1-4 heteroatoms, each of which isindependently selected from the group consisting of nitrogen, oxygen andsulfur.
 30. The compound according to claim 29, wherein ring A is of theformula

unsubstituted or substituted with said 1-5 substituents of ring A. 31.The compound according to claim 20, wherein ring A is selected from thegroup consisting of (C₇)alicyclyl, hetero(C₃₋₆)alicyclyl,(C₁₀₋₁₁)bicycloalicyclyl, and hetero(C₆₋₁₀)bicycloalicyclyl, eachunsubstituted or substituted with said 1-5 substituents, wherein thehetero(C₃₋₆)alicyclyl is a seven-membered heterocycloalkyl; the(C₁₀₋₁₁)bicycloalicyclyl comprises a first ring that is a seven-memberedalicyclyl, and a second ring that is selected from the group consistingof five, six and seven membered cyclyl; thehetero(C₆₋₁₀)bicycloalicyclyl comprises a first ring that is aseven-membered heteroalicyclyl and a second ring that is selected fromthe group consisting of five, six and seven membered cyclyl; and eachhetero(C₃₋₆)alicyclyl and hetero(C₆₋₁₀)bicycloalicyclyl contains 1-4heteroatoms, each of which is independently selected from the groupconsisting of nitrogen, oxygen and sulfur.
 32. The compound according toclaim 31, wherein ring A is of the formula

unsubstituted or substituted with said 1-5 substituents of ring A. 33.The compound according to claim 1, wherein each of said 1-5 substituentsof ring A is independently selected from the group consisting of halo,cyano, hydroxy, oxy, oxo, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,carbonylamino, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, (C₁₋₁₀)alkyl,(C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)alicyclic, hetero(C₃₋₁₂)alicyclic, (C₄₋₁₂)aryl, andhetero(C₁₋₁₀)aryl, each unsubstituted or substituted.
 34. The compoundaccording to claim 1, wherein each of said 1-5 substituents of ring A isindependently selected from the group consisting of hydroxyl, oxo, halo,cyano, (C₁₋₆)alkyl, (C₁₋₆)alkenyl, (C₁₋₆)alkynyl, halo(C₁₋₆)alkyl,(C₁₋₆)alkylcarbonylamino, (C₁₋₆)alkylaminocarbonyl, (C₁₋₆)alkoxy, amino,hydroxy(C₁₋₆)alkyl, (C₁₋₆)alkoxy(C₁₋₆)alkyl, (C₁₋₆)alkylcarbonyl,aminocarbonyl, hydroxylcarbonyl, and (C₁₋₆)alkylsulfonyl, eachunsubstituted or substituted.
 35. The compound according to claim 1,wherein each of said 1-5 substituents of ring A is independentlyselected from the group consisting of hydroxyl, fluoro, chloro, cyano,oxo, methoxy, methyl, ethyl, hydroxymethyl, perfluoromethyl,methoxymethyl, methylcarbonylamino, methylaminocarbonylamino,aminocarbonyl, methylcarbonyl, hydroxycarbonyl, and methylsulfonyl. 36.The compound according to claim 1, wherein ring A is selected from thegroup consisting of


37. The compound according to claim 1, wherein ring A is selected fromthe group consisting of


38. The compound according to claim 1, wherein ring A is selected fromthe group consisting of


39. The compound according to claim 1, wherein ring A is selected fromthe group consisting of


40. The compound according to claim 1, wherein ring A is of the formula


41. The compound according to claim 1, wherein ring A is selected fromthe group consisting of


42. The compound according to claim 1, wherein R₂ is selected from thegroup consisting of hydrogen, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl(C₁₋₃)alkyl,hetero(C₁₋₅)cycloalkyl(C₁₋₃)alkyl, (C₃₋₆)cycloalkyl, andhetero(C₁₋₅)cycloalkyl, each substituted or unsubstituted.
 43. Thecompound according to claim 1, wherein R₂ is hydrogen.
 44. The compoundaccording to claim 1, wherein R₃ is selected from the group consistingof hydrogen, hydroxyl, amino, thio, oxy, (C₁₋₆)alkyl, (C₁₋₆)cycloalkyl,and (C₁₋₆)alkoxy, each unsubstituted or substituted with 1-2substituents each of which is independently selected from the groupconsisting of hydroxyl, halo, halo(C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, hetero(C₁₋₅)cycloalkyl, phenyl, and hetero(C₁₋₅)aryl.45. The compound according to claim 1, wherein R₃ is selected from thegroup consisting of hydrogen, methyl, ethyl, cyclopropyl, and methoxy.46. The compound according to claim 1, wherein R₃ is hydrogen.
 47. Thecompound according to claim 1, wherein R₃ is methyl.
 48. A compoundconsisting of the formula

wherein ring A is selected from the group consisting of (C₅₋₇)alicyclic,hetero(C₁₋₆)alicyclic, (C₈₋₁₁)bicycloalicyclic, andhetero(C₄₋₁₀)bicycloalicyclic, (C₆)aryl, hetero(C₁₋₅)aryl,(C₈₋₁₀)bicycloaryl, and hetero(C₄₋₁₀)bicycloaryl, each unsubstituted orsubstituted with 1-5 substituents that are each independently selectedfrom the group consisting of hydroxyl, oxo, halo, cyano, (C₁₋₆)alkyl,(C₁₋₆)alkenyl, (C₁₋₆)alkynyl, halo(C₁₋₆)alkyl, (C₁₋₆)alkylcarbonylamino,(C₁₋₆)alkylaminocarbonyl, (C₁₋₆)alkoxy, amino, hydroxy(C₁₋₆)alkyl,(C₁₋₆)alkoxy(C₁₋₆)alkyl, (C₁₋₆)alkylcarbonyl, aminocarbonyl,hydroxylcarbonyl, and (C₁₋₆)alkylsulfonyl, each unsubstituted orsubstituted; R₃ is selected from the group consisting of hydrogen,methyl, ethyl, cyclopropyl, and methoxy; and R₇, R₈, R₉, R₁₀, and R₁₁are each independently selected from the group consisting of hydrogen,hydroxyl, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, —C(CH₃)(OH)CF₃, (C₁₋₆)alkoxy,halo, cyano,

where k is 1, 2, 3, or 4; and R₂₁ is selected from the group consistingof hydroxyl, (C₁₋₄)alkyl, halo(C₁₋₄)alkyl, alkyloxy, —(CH₂)_(n)OH, —CF₃,—(CH₂)_(n)CN, —(CH₂)_(n)COOH, —(CH₂)_(n)CONH₂, —(CH₂)_(n)heteroaryl, and—(CH₂)_(n)O(CH₂)_(n)heteroaryl, where n is 0, 1, 2, 3, or
 4. 49. Thecompound according to claim 48, wherein R₃ is hydrogen.
 50. The compoundaccording to claim 48, wherein R₉ is independently selected from thegroup consisting of hydrogen, t-butyl, —C(CH₃)(OH)CF₃, —C(OH)(CH₃)₂, and—C(CH₂OH)(CH₃)₂; and R₇, R₈, R₁₀, and R₁₁ are each hydrogen.
 51. Thecompound according to claim 48, wherein R₉ is —C(OH)(CH₃)₂, and R₇, R₈,R₁₀, and R₁₁ are each hydrogen.
 52. The compound according to claim 48,wherein R₉ is —C(CH₂OH)(CH₃)₂, and R₇, R₈, R₁₀, and R₁₁ are eachhydrogen.
 53. The compound according to claim 48, wherein ring A isselected from the group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.54. The compound according to claim 48, wherein ring A is selected fromthe group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.55. The compound according to claim 48, wherein ring A is selected fromthe group consisting of

each unsubstituted or substituted with said 1-5 substituents of ring A.56. The compound according to claim 48, wherein ring A is selected fromthe group consisting of


57. The compound according to claim 48, wherein ring A is selected fromthe group consisting of


58. The compound according to claim 1 selected from the group consistingof:N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-cyclopropylbenzamide;N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)nicotinamide;N-(5-(1H-imidazol-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-tert-butylbenzamide;4-tert-butyl-N-(5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;N-(5-(1H-imidazol-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-tert-butylbenzamide;N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide;N-(5-(3,5-dimethyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;N-(5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-acetylbenzamide;N-(5-(1H-pyrazol-4-yl)thiazolo[5 ,4-b]pyridin-2-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(1-methyl-1H-pyrazol-5-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;methyl4-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-ylcarbamoyl)benzoate;4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;N-(5-(2-ethyl-1H-imidazol-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;methyl4-(5-(3-ethyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-ylcarbamoyl)benzoate;4-(2-hydroxypropan-2-yl)-N-(5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-(5-(3-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(3-methylpyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(4-(methylcarbamoyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)benzamide;4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(2-methoxypyrimidin-5-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;N-(5-(6-acetamidopyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;N-(5-(2-fluoropyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide;N-(5-(6-aminopyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide;4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(6-hydroxypyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;4-(1-hydroxy-2-methylpropan-2-yl)-N-(5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(6-hydroxypyridin-3-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;(R)-4-(2-hydroxypropan-2-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-morpholinothiazolo[5,4-b]pyridin-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(piperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(3-oxopiperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;N-(5-(2-chloropyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(2-methoxypyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(piperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;N-(5-(4-(hydroxymethyl)piperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;N-(5-(6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(5-oxo-1,4-diazepan-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(4-methoxypiperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(4-methylpiperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;(S)-4-(2-hydroxypropan-2-yl)-N-(5-(2-(methoxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;N-(5-(4-acetylpiperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;(R)-4-(2-hydroxypropan-2-yl)-N-(5-(2-(methoxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;N-(5-(3-cyanopiperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;N-(5-(4-hydroxypiperidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;(S)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-2-carboxamide;(R)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-2-carboxamide;4-(2-hydroxypropan-2-yl)-N-(5-(4-oxo-3,4,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(5H)-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;(S)-N-(5-(2-(hydroxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;(S)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-3-carboxylic acid;(R)-1-(2-(4-(2-hydroxypropan-2-yl)benzamido)thiazolo[5,4-b]pyridin-5-yl)pyrrolidine-3-carboxylicacid;N-(5-(3-(hydroxymethyl)pyrrolidin-1-yl)thiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide;4-(2-hydroxypropan-2-yl)-N-(5-(4-(methylsulfonyl)piperazin-1-yl)thiazolo[5,4-b]pyridin-2-yl)benzamide;and4-(2-hydroxypropan-2-yl)-N-(5-(1,1-dioxothiomorpholino)thiazolo[5,4-b]pyridin-2-yl)benzamide.59. A pharmaceutical composition comprising as an active ingredient acompound according to claim 1 and a pharmaceutically acceptable carrier.60. A method of treating a disease state for which ASK1 possessesactivity that contributes to the pathology and/or symptomology of thedisease state, the method comprising administering a compound of claim 1to a subject, wherein the compound is present in the subject in atherapeutically effective amount for the disease state.
 61. A method oftreating a disease state comprising administering a compound of claim 1to a subject in need thereof, wherein the disease state is selected fromthe group consisting of etabolic diseases, inflammatory diseases,neurodegenerative diseases, autoimmune diseases, destructive bonedisorders, infectious diseases, diseases and conditions that aremediated by inducible pro-inflammatory proteins, reperfusion/ischemia instroke, cardiac hypertrophy, respiratory diseases, heart attacks,myocardial ischemia, organ hypoxia, vascular hyperplasia, cardiachypertrophy, hepatic ischemia, liver disease, congestive heart failure,pathologic immune responses, thrombin-induced platelet aggregation,gastroenterological diseases, hematological diseases, and urologicaldiseases.
 62. A method of treating a disease state comprisingadministering a compound of claim 1 to a subject in need thereof,wherein the disease state is selected from the group consisting ofdiabetes, type 2 diabetes mellitus, diabetic dislipidemia, impairedglucose tolerance (IGT), impaired fasting plasma glucose (IFG),metabolic acidosis, ketosis, appetite regulation, obesity andcomplications associated with diabetes including diabetic neuropathy,diabetic retinopathy, inflammatory bowel disease, Crohn's disease,chemotherapy-induced enteritis, oral mucositis, Shortened BowelSyndrome, kidney disease, hyperlipidemia, arteriosclerosis;hypertension; myocardial infarction, angina pectoris, cerebralinfarction, cerebral apoplexy and metabolic syndrome.
 63. A method oftreating a disease state comprising administering a compound of claim 1to a subject in need thereof, wherein the disease state is selected fromthe group consisting of acute pancreatitis, chronic pancreatitis,asthma, allergies, chronic obstructive pulmonary disease, adultrespiratory distress syndrome.
 64. A method of treating a disease statecomprising administering a compound of claim 1 to a subject in needthereof, wherein the disease state is selected from the group consistingof Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis (ALS), epilepsy, seizures, Huntington's disease, polyglutaminediseases, traumatic brain injury, ischemic and hemorrhaging stroke,cerebral ischemias or neurodegenerative disease, includingapoptosis-driven neurodegenerative disease, caused by traumatic injury,acute hypoxia, ischemia or glutamate neurotoxicity.
 65. A method oftreating a disease state comprising administering a compound of claim 1to a subject in need thereof, wherein the disease state is selected fromthe group consisting of glomerulonephritis, rheumatoid arthritis,systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves'disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia,autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronicactive hepatitis, myasthenia gravis, multiple sclerosis, inflammatorybowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs.host disease, multiple sclerosis, or Sjoegren's syndrome.
 66. A methodof treating a disease state comprising administering a compound of claim1 to a subject in need thereof, wherein the disease state is selectedfrom the group consisting of osteoporosis, osteoarthritis and multiplemyeloma-related bone disorder.
 67. A method of treating a disease statecomprising administering a compound of claim 1 to a subject in needthereof, wherein the disease state is selected from the group consistingof sepsis, septic shock, and Shigellosis.
 68. A method of treating adisease state comprising administering a compound of claim 1 to asubject in need thereof, wherein the disease state is selected from thegroup consisting of edema, analgesia, fever and pain, such asneuromuscular pain, headache, cancer pain, dental pain, and arthritispain.
 69. A method of treating a disease state comprising administeringa compound of claim 1 to a subject in need thereof, wherein the diseasestate is selected from the group consisting of ischemia/reperfusion instroke, heart attacks, myocardial ischemia, organ hypoxia, vascularhyperplasia, cardiac hypertrophy, hepatic ischemia, liver disease,congestive heart failure, pathologic immune responses such as thatcaused by T cell activation, and thrombin-induced platelet aggregation.